NZ621471B2 - Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof - Google Patents

Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof Download PDF

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NZ621471B2
NZ621471B2 NZ621471A NZ62147112A NZ621471B2 NZ 621471 B2 NZ621471 B2 NZ 621471B2 NZ 621471 A NZ621471 A NZ 621471A NZ 62147112 A NZ62147112 A NZ 62147112A NZ 621471 B2 NZ621471 B2 NZ 621471B2
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New Zealand
Prior art keywords
acid
stage
phenyl
added
chloro
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NZ621471A
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NZ621471A (en
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Christopher John Brown
Stephen Martin Courtney
Aguiar Pena Paula C De
Celia Dominguez
Peter Johnson
William Mitchell
Ignacio Munoz
Michael Prime
Leticia M Toledosherman
Sherman Leticia M Toledo
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Chdi Foundation Inc
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Priority to NZ718150A priority Critical patent/NZ718150B2/en
Priority claimed from PCT/US2012/052648 external-priority patent/WO2013033085A1/en
Publication of NZ621471A publication Critical patent/NZ621471A/en
Publication of NZ621471B2 publication Critical patent/NZ621471B2/en

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Abstract

Disclosed herein is the compound 6-(3-chloro-4-cyclopropoxy-phenyl)-pyrimidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical compositions comprising a compound of formula I and one or more pharmaceutically acceptable excipients. The compounds are intended for the treatment of conditions mediated by kynurenine 3-monooxygenase, which include neurodegenerative disorders such as Huntington's disease. intended for the treatment of conditions mediated by kynurenine 3-monooxygenase, which include neurodegenerative disorders such as Huntington's disease.

Description

KynurenineMonooxygenase Inhibitors, Pharmaceutical Compositions, and Methods of Use Thereof This applications claims the benefit of ty ofUS. Application No. 61/528,998, filed August 30, 2011, which is incorporated herein in its ty for all purposes.
Provided herein are certain kynureninem0n00xygenase inhibitors, pharmaceutical compositions thereof, and methods of their use.
Kynurenine-3 -monooxygenase (KMO) is an enzyme in the tryptophan degradation pathway that catalyzes the sion of nine (KYN) into 3- hydroxykynurenine (3-HK), which is further degraded to the excitotoxic NMDA receptor agonist QUIN (3-hydr0xyanthranilate oxygenase). 3-OH-KYN and QUIN act synergistically, i.e. 3-OH-KYN significantly potentiates the excitotoxic actions of QUIN.
Studies from several laboratories have provided evidence that the shift of KYN y metabolism away from the 3-OH-KYN/QUIN branch to increase the formation of the neuroprotectant KYNA in the brain leads to neuroprotection. In addition to having effects in the brain, the inhibition ofKMO is filrther contemplated to impact peripheral s.
Thus, the inhibition ofKMO may be useful in the treatment of peripheral diseases as well as diseases of the brain. Furthermore, the relationship between KMO inhibition and elevations in AA (Anthranilic acid) could also have significant biological effects.
It has also been reported that KMO expression increases in inflammatory ions or after immune stimulation. 3-OH-KYN, the product of its ty, accumulates in the brain of n B-6 deficient neonatal rats and it causes cytotoxicity when added to al cells in primary cultures or when locally injected into the brain.
Recently, it was reported that relatively low concentrations (nanomolar) of 3-OH-KYN may cause apoptotic cell death of neurons in primary neuronal cultures. Structure-activity studies have in fact shown that 3-OH-KYN, and other o-amino phenols, may be subject to oxidative reactions initiated by their conversion to quinoneimines, a process associated with concomitant tion of oxygen-derived free radicals. The involvement of these reactive s in the pathogenesis of ischemic neuronal death has been widely studied in the last l years and it has been shown that oxygen derived free radicals and glutamate mediated neurotransmission co-operate in the development of ischemic neuronal death.
It was also recently demonstrated that KMO activity is particularly elevated in the iris-ciliary body and that rmed 3-OH-KYN is secreted into the fluid of the lens. An excessive accumulation of 3-OH-KYN in the lens may cause cataracts.
QUIN is an agonist of a subgroup of NMDA receptors and when directly injected into brain areas it destroys most neuronal cell bodies sparing fibers en passant and neuronal terminals. QUIN is a relatively poor agonist of the NMDA or complex containing either NR2C or NR2D subunits, while it interacts with relatively high y with the NMDA receptor complex containing NR2A and NRZB subunits. The oxicity profile found after intrastriatal injection of QUIN les that found in the basal nuclei of Huntington's disease patients: while most of the intrinsic al neurons are destroyed, NADH-diaphorase-staining neurons (which are now ered able to express nitric oxide synthetase) and neurons containing eptide Y seem to be spared together with axon terminals and fiber en passant.
In vivo- infusion ofKYNA has shown to modulate synaptic release of critical neurotransmitters implicated in ive processes and affective mental faculties, such as Acetylcholine, dopamine, and glutamate; therefore elevation ofKYNA in brain can have effects in cognitive disorders and disorders arising from, or influenced by, changes in the levels of the neurotransmitters glutamate, dopamine, or Ach (such as Alzheimers, MCI, PD, schizophrenia, HD, OCD, Tourette’s).
In vitro, the neurotoxic effects of the compound have been studied in ent model systems with variable results: chronic exposure of organotypic o- striatal es to submicromolar concentration of QUIN causes histological signs of pathology, similar results have been obtained after c exposure of cultured neuronal cells.
In models of inflammatory neurological disorders such as experimental allergic encephalitis, bacterial and viral infections, forebrain global ischemia or spinal trauma, brain QUIN levels are extremely elevated. This increased brain QUIN concentration could be due to either an elevated circulating concentration of the excitotoxin or to an increased de novo synthesis in activated microglia or in infiltrating macrophages. In retrovirus-infected macaques, it has been proposed that most of the increased content of brain QUIN (approximately 98%) is due to local tion. In fact, a robust increase in the activities of IDO, KMO and kynureninase has been found in areas of brain inflammation.
Previous studies have shown that agents able to increase brain KYNA content cause on, mild sia, increase in the convulsive threshold and neuroprotection against excitotoxic or ic damage. In addition to the above reported evidences, it has been recently trated that a number of compounds able to increase brain KYNA formation may cause a robust decrease in glutamate (GLU) mediated neurotransmission by reducing GLU concentrations in brain extracellular spaces.
There remains a need for compounds that are effective inhibitors ofKMO and may be used in treating neurodegenerative disorders.
Provided is at least one chemical entity chosen from compounds of Formula I and pharmaceutically acceptable salts and prodrugs thereof wherein: X and Y are independently chosen from —N— and —CH—, provided that at least one ofX and Y is —N—; R1 is aryl or monocyclic heteroaryl, each of which is substituted with a first group of the formula —Z-R6 n Z is chosen from O S , , S(O) , S(O)2 , CR11R12—, —OCR11R12—, —NR13—, —NR13CR11R12—, —CR11R12NR13—, —C(O)— where R11, R12, and R13 are independently chosen from hydrogen, lower alkyl, hydroxyl, and lower , R6 is chosen from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that if Z is —O—, then R6 is not optionally tuted benzyl or optionally substituted pyridylniethyl, or R6 and R13, taken together with the nitrogen to which they are bound form an optionally substituted 5- to 7-men1bered heterocycloalkyl ring, and a second group chosen from halo and lower alkyl optionally substituted with halo, or R1 is chosen from 2,3-dihydrobenzofuranyl, chromanyl, l,3-benzodioxol yl, 2,3-dihydro-l,4-benzodioxinyl, l,3-benzoxazolyl, benzoiniidazol- -yl, l,3-benzoxazolyl, 2-oxo-2,3-dihydro-l ,3-benzoxazolyl, benzothiophen-S-yl, benzothiazol-S-yl, benzofuran-S-yl, lH-indol-S-yl, lH-indazol-S-yl, isoindolinyl, benzo[c][l,2,5]oxadiazolyl, l,2,3,4- tetrahydroquinolinyl, in1idazo[ l ,2-a]pyridinyl, pyrazolo[ l ,5 - dineyl, quinolinyl, quinazolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally substituted, or R1 and R3, taken together with intervening atoms form a bicyclic ring of the formula “V; ”21, 5V >m which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided that at least one ofm and n is l and W is —O-, or —N(Rg)- where R8 is hydrogen or lower alkyl; R2 is chosen from hydrogen and optionally tuted lower alkyl; R3 is chosen from hydrogen, halo, optionally substituted lower alkyl, hydroxyl, optionally substituted lower alkoxy, and ally substituted amino; L is chosen from -C(O)-, -, -C(O)N(R4)-, -C(O)N(OR7)-, S(O)2-, -S(0)2N(R4)-, and-C(0)N(R4)-S(0)2-; R4 is chosen from hydrogen and lower alkyl; R5 is chosen from hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally tuted cycloalkyl, and optionally tuted heterocycloalkyl; provided that when L is -N(R4)S(O)2-, then R5 is not hydrogen, or R4 and R5 taken together with the nitrogen to which they are bound form an optionally tuted 4- to 7-membered cycloalkyl ring, which is optionally fused to an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or ally substituted heteroaryl ring; or R3 and R5, taken together with the intervening atoms, form an optionally substituted 5- to 7-membered ring; and R7 is chosen from hydrogen and lower alkyl; provided that the compound of a I is not chosen from 6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid methyl ester; 6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid; 6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester; and 6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid.
Also provided is a pharmaceutical composition comprising at least one al entity described herein and at least one pharmaceutically able excipient.
Also provided is a method of treating a condition or disorder mediated by Kynurenine 3-mono-oxygenase activity in a subject in need of such a treatment which method comprises stering to the subject a therapeutically effective amount of at least one chemical entity described .
Also provided is a method of treating a condition or disorder mediated by nine 3-mono-oxygenase activity in a subject in need of such a treatment which method comprises administering to the t a therapeutically effective amount of at least one chemical entity described herein.
Also provided is a packaged pharmaceutical composition sing at least one pharmaceutical composition described herein and instructions for using the composition to treat a subject suffering from a condition or disorder mediated by Kynurenine 3-mono-oxygenase activity.
As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout: A dash (“-“) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For e, -CONH2 is attached through the carbon atom.
By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and ces in which it does not. For e, “optionally substituted alkyl” encompasses both “alkyl” and ituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or tution patterns that are sterically impractical, synthetically non- feasible and/or inherently le.
“Alkyl” encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as l to 6 carbon atoms. For example C1-C6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. Alkylene is another subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, C0 alkylene indicates a covalent bond and C1 alkylene is a methylene group. When an alkyl residue having a c number of carbons is named, all geometric isomers having that number of s are intended to be encompassed; thus, for example, "butyl" is meant to include n- butyl, sec-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and pyl. “Lower alkyl” refers to alkyl groups having 1 to 4 carbons.
“Cycloalkyl” indicates a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as well as bridged and caged saturated ring groups such as norbomane.
By “alkoxy” is meant an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, y, isopropoxy, n-butoxy, sec-butoxy, utoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, , 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. An alkoxy group is further meant to encompass a cycloalkyl group, as defined above, that is likewise attached through an oxygen bridge. Alkoxy groups will usually have from 1 to 6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy groups having 1 to 4 carbons.
“Aryl” encompasses: - and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring s wherein at least one ring is carbocyclic and aromatic, for example, alene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is yclic and aromatic, for example, fluorene.
For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to ered heterocycloalkyl ring containing 1 or more heteroatoms chosen from N, O, and S, ed that the point of attachment is at the carbocyclic aromatic ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one en atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not ass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as d herein.
The term “halo” includes fluoro, chloro, bromo, and iodo, and the term “halogen” includes fluorine, chlorine, bromine, and iodine.
“Heteroaryl” asses: - to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or In some embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon; and bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or In some embodiments, from 1 to 3, atoms chosen from N, O, and S, with the ing ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For e, heteroaryl also includes a 5- or 6-membered cycloalkyl, aromatic ring fused to a 5- to 7-membered aryl ring.
For such fused, bicyclic aryl ring systems wherein only one of the rings contains one or more atoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not d to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, dyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, idazolinyl, isoxazolyl, isoxazolinyl, oxazolyl, oxazolinyl, oxadiazolyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, benzooxazolyl, nyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8- tetrahydroisoquinoline. Bivalent radicals derived from univalent aryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.
Substituted heteroaryl also includes ring s substituted with one or more oxide (-0") substituents, such as pyridinyl es.
By “heterocycloalkyl” is meant a single aliphatic ring, y with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. “Heterocycloalkyl” also refers to 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms chosen from N, O, and S, provided that the point of attachment is at the heterocycloalkyl ring. Suitable heterocycloalkyl groups e, for example (as ed from the linkage position assigned priority 1), 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5- piperzinyl. linyl groups are also contemplated, including 2-morpholinyl and 3- morpholinyl (numbered wherein the oxygen is assigned priority 1). Substituted heterocycloalkyl also es ring systems substituted with one or more oxo moieties, such as piperidinyl N—oxide, morpholinyl-N-oxide, l-oxo-l-thiomorpholinyl and 1,1- dioxo- l -thiomorpholinyl.
The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not ed. When a tuent is oxo (i.e., =0) then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a on mixture, and subsequent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this tuent to the core structure is in the alkyl portion.
The terms “substituted” alkyl (including without limitation lower alkyl), cycloalkyl, aryl (including without limitation phenyl), heterocycloalkyl (including without limitation linyl, 3 ,4-dihydroquinolin- l (2H)-yl, indolin- l -yl, 3 -oxopiperazin- l - yl, piperidin-l-yl, piperazin-l-yl, pyrrolidin-l-yl, azetidin-l-yl, and isoindolinyl), and heteroaryl ding without limitation pyridinyl), unless otherwise expressly defined, refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent ndently chosen from: -Ra, -ORb, -O(C1-C2 alkyl)O- (e.g., methylenedioxy-), -SRb, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRbR°, halo, cyano, oxo (as a substituent for heterocycloalkyl), nitro, -CORb, , -CONRbR°, -OCORb, -OC02Ra, -OCONRbR°, -NR°CORb, -NR°C02Ra, -NR°CONRbR°, -SORa, —sozRa, -SOzNRbR°, and -NR°SOzRa, where Ra is chosen from optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally tuted heteroaryl; Rb is chosen from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally tuted heterocycloalkyl, and ally substituted heteroaryl; and Rc is chosen from hydrogen and optionally substituted C1-C4 alkyl; or Rb and RC, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-Cl-C4 alkyl, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NHZ, C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl), -C02H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 , -CONH2, -NHC(O)(C1-C4 alkyl), )(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, 1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SOZ(C1-C4 alkyl), - SOz(phenyl), -SOz(C1-C4 haloalkyl), -SOzNH2, -SOZNH(C1-C4 alkyl), (phenyl), - NHSOz(C1-C4 alkyl), -NHSOz(phenyl), and (C1-C4 haloalkyl).
The term “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is tuted (i.e., -O-(substituted alkyl)) wherein “substituted alkyl” is as described herein. “Substituted ” also includes glycosides (i.e., glycosyl groups) and derivatives of ascorbic acid.
The term “substituted amino” refers to the group —NHRd or —NRdRd where each Rd is independently chosen from: hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, aminocarbonyl, optionally substituted aryl, optionally substituted aryl, ally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, each as described herein, and provided that only one Rd may be yl. The term “substituted amino” also refers to N—oxides of the groups —NHRd, and NRdRd each as described above. N-oxides can be ed by treatment of the corresponding amino group with, for example, hydrogen peroxide or m- chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N—oxidation. carbonyl” encompasses a group of the a —(C=O)(optionally substituted amino) wherein substituted amino is as described herein.
“Acyl” refers to the groups (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)- ; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the ed carbon atoms. For example a C2 acyl group is an acetyl group haVing the formula O)-.
By ycarbonyl” is meant an ester group of the formula (alkoxy)(C=O)— attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a C1-C6alkoxycarbonyl group is an alkoxy group haVing from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
By “amino” is meant the group -NH2.
The term “sulfmyl” includes the groups: -S(O)-(optionally substituted (C1- C6)alkyl), -S(O)-optionally tuted aryl), -S(O)-optionally tuted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino).
The term “sulfonyl” includes the groups -S(02)-(optionally substituted (C1- C6)alkyl), -S(02)-optionally substituted aryl), -S(02)-optionally substituted heteroaryl), - S(02)-(optionally substituted heterocycloalkyl), -S(02)-(optionally substituted alkoxy), -S(02)-optionally substituted aryloxy), -optionally substituted heteroaryloxy), -S(02)-(optionally substituted heterocyclyloxy); and -S(02)-(optionally substituted amino).
The term ituted acyl” refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)—C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)—; and (substituted heterocycloalkyl)-C(O)—, wherein the group is attached to the parent structure through the carbonyl fianctionality and wherein substituted alkyl, lkyl, aryl, aryl, and heterocycloalkyl are as described herein.
The term ituted carbonyl” refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl fianctionality and wherein tuted alkyl is as described herein.
“Glycosides” refer to any of a number of sugar derivatives that contain a non-sugar group bonded to an oxygen or nitrogen atom of a sugar and that on hydrolysis yield that sugar. An example of a glycosyl group is glucosyl.
“Derivatives of ascorbic acid” or “ascorbic acid tives” refer to any of a number of derviatives that contain a non-sugar group bonded to an oxygen or nitrogen atom of ascorbic acid and that on hydrolysis yield ascorbic acid (i.e., (R)((S)-l,2- dihydroxyethyl)-3 ,4-dihydroxyfuran-2(5H)-one).
Compounds described herein e, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as llization in the presence of a resolving agent, or chromatography, using, for example a chiral high- pressure liquid chromatography (HPLC) . In addition, such compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds.
Where compounds described herein exist in various tautomeric forms, the term “compound” is intended to include all tautomeric forms of the compound. Such compounds also include crystal forms including polymorphs and ates. Similarly, the term “salt” is intended to include all tautomeric forms and crystal forms of the compound.
Chemical entities include, but are not limited to compounds described herein and all pharmaceutically acceptable forms thereof. ceutically able forms of the compounds recited herein include pharmaceutically acceptable salts, prodrugs, and es f In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts and prodrugs. Hence, the terms “chemical entity” and “chemical entities” also encompass pharmaceutically acceptable salts, prodrugs, and mixtures thereof “Pharmaceutically able salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulf1nate, e, and like salts; as well as salts with an organic acid, such as malate, maleate, filmarate, te, succinate, citrate, acetate, lactate, esulfonate, enesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and ate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt.
Conversely, if the product is a free base, an addition salt, particularly a ceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the on with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to e non-toxic pharmaceutically acceptable addition salts.
As noted above, prodrugs also fall within the scope of chemical entities described herein. In some embodiments, the “prodrugs” described herein include any compound that becomes a nd of Formula I when administered to a t, e.g., upon metabolic processing of the prodrug. Examples of gs include derivatives of functional groups, such as a carboxylic acid group, in the compounds of Formula I.
Exemplary prodrugs of a carboxylic acid group e, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl . Other exemplary prodrugs e lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.
Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include metabolically labile amides that are formed, for example, with an amine and a carboxylic acid. ary amines include NH2, primary, and secondary amines such as NHRX, and NRXRy, wherein RX is hydrogen, (C1-C18)-alkyl, (C3-C7)- lkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl-, (C6-C14)-aryl which is unsubstituted or substituted by a residue (C1-C2)-alkyl, (C1-C2)-alkoxy, fluoro, or chloro; heteroaryl-, (C6- C14)-aryl-(C1-C4)-alkyl- where aryl is unsubstituted or substituted by a residue (C1-C2)- alkyl, (C1-C2)-alkoxy, fluoro, or chloro; or heteroaryl-(Cl-C4)-alkyl- and in which Ry has the meanings indicated for RX with the exception of hydrogen or wherein RK and Ry, together with the nitrogen to which they are bound, form an ally substituted 4- to 7- membered heterocycloalkyl ring which optionally includes one or two additional heteroatoms chosen from nitrogen, oxygen, and sulfur. A discussion of prodrugs is ed in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American ceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
A “solvate” is formed by the interaction of a solvent and a compound. The term und” is intended to include solvates of compounds. Similarly, “salts” includes solvates of salts. Suitable es are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. The term “compound” is ed to include es of compounds. Similarly, “salts” includes chelates of salts.
A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non- covalent complexes are included in the term “compound’.
The term gen bond" refers to a form of association n an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, vely electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry (G. C. el and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. d, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp. 320-326 (1984)).
“Hydrogen bond acceptor” refers to a group comprising an oxygen or nitrogen, such as an oxygen or en that is sp2 —hybridized, an ether , or the oxygen of a ide or N—oxide.
The term "hydrogen bond donor" refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen.group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.
As used herein the terms "group", "radical" or "fragment" are synonymous and are intended to indicate functional groups or fragments of molecules able to a bond or other fragments of molecules.
The term “active agent” is used to indicate a chemical entity which has biological activity. In some embodiments, an “active agent” is a compound having pharmaceutical utility. For example an active agent may be an anti-neurodegenerative therapeutic.
The term "therapeutically effective amount" of a chemical entity described herein means an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease e.g., a therapeutically effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition ofKMO activity and modulation of kynurenine pathway metabolites (such as kynurenine, kynurenic acid, anthranilic acid, 3-OH-kynurenine, 3-OH anthranilic acid, or quinolinic acid). In some embodiments, a eutically effective amount is an amount sufficient to treat the symptoms of neurodegenerative y or disease. In some embodiments a therapeutically ive amount is an amount sufficient to reduce the signs or side effects of a neurodegenerative disease. In some embodiments, a therapeutically effective amount of a chemical entity is an amount ent to prevent a significant increase or significantly reduce the level of neuronal cell death. In some embodiments, a therapeutically effective amount of a al entity is an amount sufficient to prevent a cant increase or significantly reduce the level of QUIN associated with neuronal cell death. In some embodiments, a therapeutically effective amount of a chemical entity is an amount sufficient to effect an increase in the level of KYNA associated with al cell health. In some embodiments, a therapeutically effective amount of a chemical entity is an amount ent to increase the anticonvulsant and neuroprotective properties associated with lowered levels of QUIN and increased levels of KYNA. In some embodiments, a therapeutically effective amount is an amount sufficient to modulate an inflammatory process in the body, ing but not limited to inflammation in the brain, spinal cord, and peripheral nervous sytem, or meninges. In some embodiments, a therapeutically effective amount is an amount sufficient to modulate the production of cytokines responsible for mounting an effective immune response (such as IL-l beta or TNF-alpha) or an amount ent to affect te/macrophage pro- inflammatory ty in the periphery or in the brain in conditions where the blood-brain barrier is compromised, such as in multiple sclerosis).
In methods described herein for treating a neurodegenerative disorder, a therapeutically effective amount may also be an amount sufficient, when administered to a patient, to detectably slow the ssion of the neurodegenative disease, or prevent the patient to whom the chemical entity is given from presenting symptoms of the neurodegenative disease. In some methods described herein for treating a neurodegenative disease, a therapeutically effective amount may also be an amount sufficient to produce a detectable decrease in the level of neuronal cell death. For e, in some ments a therapeutically effective amount is an amount of a chemical entity bed herein sufficient to significantly decrease the level of neuronal death by effecting a detectable decrease in the amount of QUIN, and an increase in the amount of kynurenine, KYNA, or anthranilic acid.
In addition, an amount is considered to be a therapeutically effective amout if it is characterized as such by at least one of the above criteria or experimental ions, regardless of any inconsistent or contradictory results under a different set of criteria or experimental conditions.
The term “inhibition” indicates a significant decrease in the baseline activity of a biological ty or process. “Inhibition ofKMO activity” refers to a decrease in KMO activity as a direct or indirect response to the presence of at least one chemical entity described herein, relative to the activity ofKMO in the absence of at least one chemical entity. The se in activity may be due to the direct interaction of the compound with KMO, or due to the interaction of the chemical entity(ies) described herein with one or more other s that in turn affect KMO ty. For example, the presence of the chemical (ies) may decrease KMO activity by directly binding to the KMO, by causing (directly or indirectly) another factor to decrease KMO activity, or by (directly or indirectly) decreasing the amount ofKMO present in the cell or organism.
“Inhibition ofKMO activity” refers to a decrease in KMO ty as a direct or indirect response to the presence of at least one chemical entity described herein, relative to the activity of KMO in the absence of the at least one chemical entity. The decrease in activity may be due to the direct interaction of the compound with KMO or with one or more other factors that in turn affect KMO activity.
Inhibition ofKMO activity also refers to an observable inhibition of 3-HK and QUIN production in a standard assay such as the assay described below. The inhibition ofKMO activity also refers to an observable increase in the production of KYNA. In some embodiments, the chemical entity described herein has an IC50 value less than or equal to l micromolar. In some embodiments, the chemical entity has an IC50 value less than or equal to less than 100 olar. In some embodiments, the chemical entity has an IC50 value less than or equal to 10 nanomolar.
“KMO ty” also es activation, redistribution, reorganization, or capping of one or more various KMO membrane-associated proteins (such as those receptors found in the mitochondria), or binding sites can undergo redistribution and capping that can initiate signal transduction. KMO activity also can modulate the availability of nine, which can effect the the synthesis or production of QUIN, KYNA, anthranilic acid, and/or 3-HK.
A “disease responsive to inhibition ofKMO activity” is a disease in which inhibiting KMO provides a therapeutic t such as an amelioration of symptoms, decrease in disease progression, prevention or delay of disease onset, prevention or amelioration of an inflammatory response, or inhibition of aberrant activity and/or death of certain cell-types (such as neuronal .
“Treatment” or “treating” means any treatment of a disease in a patient, ing: a) preventing the disease, that is, causing the al symptoms of the disease not to develop; b) inhibiting the progression of the disease; c) slowing or arresting the development of clinical symptoms; and/or d) relieving the disease, that is, causing the regression of al symptoms.
“Subject” or “patient’ refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; and in some ments the t is human.
Provided is at least one al entity chosen from nds of Formula I Formula I and pharmaceutically acceptable salts and prodrugs thereof wherein: X and Y are independently chosen from —N— and —CH—, provided that at least one ofX and Y is —N—; R1 is aryl or monocyclic heteroaryl, each of which is substituted with a first group of the formula —Z-R6 wherein Z is chosen from O, S, S(O), S(O)2, 2—, —OCR11R12—, —NR13—, —NR13CR11R12—, —CR11R12NR13—, —C(O)— where R11, R12, and R13 are independently chosen from hydrogen, lower alkyl, hydroxyl, and lower alkoxy, R6 is chosen from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, provided that if Z is —O—, then R6 is not optionally substituted benzyl or optionally substituted pyridylmethyl, or R6 and R13, taken together with the nitrogen to which they are bound form an optionally substituted 5- to ered heterocycloalkyl ring, and a second group chosen from halo and lower alkyl optionally substituted with halo, or R1 is chosen from hydrobenzofuranyl, nyl, l,3-benzodioxol yl, 2,3-dihydro-l ,4-benzodioxinyl, l,3-benzoxazolyl, 1,3- benzoxazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, benzothiophen- -yl, benzothiazol-S-yl, benzoimidazol-S-yl, uran-S-yl, lH-indol-S- yl, lH-indazol-S-yl, isoindolinyl, benzo[c][l,2,5]oxadiazolyl, l ,2,3 ,4-tetrahydroquinolinyl, imidazo[ l ,2-a]pyridinyl, pyrazolo[ l ,5- a]pyridineyl, quinolinyl, quinazolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally substituted, R1 and R3, taken together with ening atoms form a bicyclic ring of the formula which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided that at least one ofm and n is l and W is —O-, or —N(Rg)- where R8 is hydrogen or lower alkyl; R2 is chosen from hydrogen and optionally substituted lower alkyl; R3 is chosen from en, halo, optionally substituted lower alkyl, yl, optionally substituted lower alkoxy, and optionally substituted amino; L is chosen from -C(O)-, -C(O)O-, -C(O)N(R4)-, (OR7)-, -N(R4)S(O)2-, - S(O)2N(R4)-, and-C(O)N(R4)-S(O)2-; R4 is chosen from en and lower alkyl; R5 is chosen from en, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cycloalkyl; provided that when L is -N(R4)S(O)2-, then R5 is not hydrogen, or R4 and R5 taken together with the nitrogen to which they are bound form an ally substituted 4- to ered heterocycloalkyl ring, which is optionally fused to an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl ring; or R3 and R5, taken together with the intervening atoms, form an optionally substituted 5- to 7-membered ring; and R7 is chosen from hydrogen and lower alkyl; provided that the compound of Formula I is not chosen from 6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid methyl ester; 6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid; 6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester; and 6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid.
In some embodiments, R1 is phenyl substituted with a first group of the formula —Z-R6 wherein Z is chosen from —O—, —S—, — S(0) —, —S(O)2—, and —CR11R12—; and R6 is chosen from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and a second group chosen from halo and lower alkyl optionally substituted with halo.
In some embodiments, R1 is pyridinyl substituted with a first group of the formula —Z-R6 wherein Z is chosen from —O—, —S—, — S(O) —, —S(O)2—, and —CR11R12—; and R6 is chosen from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and a second group chosen from halo and lower alkyl optionally substituted with halo.
In some embodiments, Z is —O—.
In some ments, Z is —S—.
In some embodiments, Z is —S(O)2—.
In some embodiments, Z is —CR11R12—.
In some embodiments, R6 is chosen from hydrogen, , difluoromethyl, trifluoromethyl, ethyl, trifluoro-l-methyl-ethyl, isopropyl, (S)-secbutyl , (R)-sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-morpholinyl-ethyl, 2- piperidin-l-yl-ethyl, idinyl, and tetrahydro-furanyl.
In some embodiments, R1 is chosen from 3-chlorocyclobutoxy-phenyl, rocyclopentyloxy-phenyl, 3-chlorocyclopropoxy-phenyl, 3-chloro isopropoxy-phenyl, 3-chloromethoxy-phenyl, [4-chloro(2-morpholinyl-ethoxy)- phenyl, 3 o(2-piperidin- l -yl-ethoxy)-phenyl, 3 -chloro(pyrrolidin-3 -yloxy)- phenyl, 4-(S)-sec-butoxychloro-phenyl, 4-(R)-sec-butoxychloro-phenyl, 4-chloro (tetrahydro-furan—3-yloxy)-phenyl, 3-chlorotrifluoromethoxy-phenyl, 3-chloro -trifluoro-l-methyl-ethoxy, 3-methoxy-phenyl, oxy-phenyl, 3,4- dimethoxyphenyl, 3-chloroisopropylphenyl, 3-fluoromethylphenyl, and 3-fluoro isopropylphenyl, 3,4-bis(methylsulfanyl)phenyl, 3,4-bis(methylsulfonyl)phenyl, 3,4- bis(trifluoromethoxy)phenyl, 3-chloro(difluoromethoxy)phenyl, 3-chloro (methylsulfanyl)phenyl, 3-chloro(methylsulfonyl)phenyl, 3-chloro (trifluoromethoxy)phenyl, 3-chloro(cyclopropoxymethyl)phenyl, 3-chloro (cyclopropylmethyl)phenyl, 3-chloro(cyclopropanesulfinyl)phenyl, 3-chloro (cyclopropanesulfonyl)phenyl, 3-chloro[cyclopropyl(hydroxy)methyl]phenyl, 3- chloro(l-cyclopropoxyethyl)phenyl, 3-chlorocyclopropanecarbonylphenyl, 3- cyclopropylphenyl, ridin-1 -y1methy1)-3 -chlorophenyl, 3 -chloro [(dimethylamino)methyl]phenyl, 3-chloro(cyclopropylamino)phenyl, 3-chloro [cyclopropy1(methyl)amino]pheny1, 3-chloro[(cyclopropylamino)methy1]phenyl, 3- chloro {[cyclopropyl(methy1)amino]methy1}phenyl, 3-chloro(1- ycyclopropy1)phenyl, 4-chloro[(1,1,1-trifluoropropany1)oxy]phenyl, 4- chloro(trifluoromethoxy)phenyl, ro(2-methy1propoxy)phenyl, 4-chloro (propan-Z-yloxy)phenyl, 4-chloro(propanyloxy)pheny1, 4-chloromethoxyphenyl, 4-chlorocyclopropoxyphenyl, and 3-chloro{[1-(morpholiny1)propan y1]oxy}pheny1.
In some embodiments, R1 is chosen from 3-chloromethoxy-pheny1, 3- chloro(trifluoromethoxy)phenyl, 3-chlorocyclobutoxy—phenyl, 3-chloro cyclopropoxy-phenyl, 3-chloroisopropoxy-phenyl, romethoxy-pheny1, 3- chloro(pyrrolidinyloxy)-phenyl, 4-(S)-sec-butoxychloro-phenyl, 4-(R)—sec- butoxy—3-chloro-pheny1, 4-chloro(tetrahydro-furanyloxy)-pheny1, 3-chloro trifluoromethoxy-phenyl, ro(2,2,2-trifluoromethy1-ethoxy, 3-methoxy—pheny1, 4-methoxy-phenyl, 3,4-dimethoxyphenyl, 3-chloroisopropylpheny1, 3-fluoro methylphenyl, and 3-fluoroisopropy1phenyl, 3,4-bis(trifluoromethoxy)phenyl, 3- chloro(difluoromethoxy)phenyl, 3-chloro(trifluoromethoxy)phenyl, 3-chloro (cyclopropoxymethy1)phenyl, 3-chloro(cyclopropylmethyl)phenyl, ro (cyclopropanesulfinyl)phenyl, 3-chloro(cyclopropanesulfony1)phenyl, 3-chloro [cyclopropyl(hydroxy)methyl]phenyl, 3-chloro(1-cyclopropoxyethyl)pheny1, ro- 4-cyclopropanecarbonylphenyl, 3-chlorocyclopropylphenyl, 4-(aziridiny1methy1)—3- chlorophenyl, 3-chloro[(dimethylamino)methy1]phenyl, 3-chloro (cyclopropylamino)phenyl, 3-chloro[cyclopropy1(methyl)amino]pheny1, 3-chloro [(cyclopropylamino)methyl]phenyl, ro {[cyclopropy1(methy1)amino]methyl}phenyl, 3-chloro(1 -methoxycyclopropyl)pheny1, 4-chloro-3 -[(1 1 1 -trifluoropropan—2-y1)oxy]phenyl, 4-chloro(trifluoromethoxy)phenyl, , , 4-chloro(2-methy1propoxy)phenyl, 4-chloro(propanyloxy)pheny1, 4-chloro (propan-Z-yloxy)phenyl, 4-chloromethoxypheny1, and 4-chloro-3 -cyclopropoxyphenyl.
In some embodiments, R1 is chosen from 1,3-benzodioxoly1, chroman- 6-yl, 2,3-dihydrobenzofuranyl, benzofuran-S-yl, 2,3-dihydro-lH-isoindol-S-yl, 1,3- benzoxazol-S-yl, 2-oxo-2,3-dihydro-1,3-benzoxazolyl, 1,3-benzoxazoly1, imidazo[1,2-a]pyridiny1, 1,3-benzoxazolyl, quinoliny1, and pyrazolo[1,5- a]pyridinyl, each of which is optionally substituted with one or two groups chosen from halo, lower alkyl optionally substituted with halo, lkyl, and lower alkoxy optionally tuted with halo.
In some embodiments, R1 is chosen from l,3-benzodioxolyl, 2,2- difluoro-l,3-benzodioxolyl, 8-chloro-chromanyl, 7-chloro-benzofuranyl, 7- chlorocyclopropyl-2,3-dihydro- l H-isoindol-S -yl, 7-chloromethyl- l ,3 xazol-5 - yl, 7-chlorooxo-2,3-dihydro-l,3-benzoxazolyl, 7-chloromethyloxo-2,3- dihydro- l ,3-benzoxazol-5 -yl, rocyclopropyl- l ,3-benzoxazolyl, 8- chloroimidazo[l,2-a]pyridinyl, 4-chloro-l,3-benzoxazolyl, quinolinyl, and pyrazolo[ l ,5-a]pyridinyl.
In some embodiments, R1 is chosen from l,3-benzodioxolyl, 2,2- difluoro-l,3-benzodioxolyl, 8-chloro-chromanyl, 7-chloro-benzofuranyl, 7- chloromethyl-l,3-benzoxazolyl, 7-chlorocyclopropyl-l,3-benzoxazolyl, 8- chloroimidazo[l,2-a]pyridinyl, 4-chloro-l,3-benzoxazolyl, quinolinyl, and pyrazolo[ l yridinyl.
In some embodiments, R2 is hydrogen.
In some embodiments, R2 is lower alkyl.
In some embodiments, R2 is methyl or ethyl.
In some embodiments, R2 is .
In some embodiments, R3 is hydrogen.
In some embodiments, R3 is fluoro or chloro.
In some embodiments, R3 is methyl.
In some embodiments, R3 is —CH2OH.
In some embodiments, X is —N—.
In some embodiments, Y is —N—.
In some embodiments, X and Y are —N—.
In some embodiments, L is -C(O)O-.
In some embodiments, L is -C(O)N(R4)—.
In some embodiments, L is -N(R4)S(O)2-.
In some embodiments, R4 is hydrogen.
In some embodiments, R5 is lower alkyl.
In some embodiments, R5 is hydrogen.
In some embodiments, R4 and R5 taken er with the nitrogen to which they are bound form an optionally substituted 5- to 7-membered heterocycloalkyl ring. In some embodiments, R4 and R5 taken together with the nitrogen to which they are bound form a ring chosen from 3-oxopiperazin-l-yl, 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)—yl, 4-oxohexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, piperidin-l-yl, azetidinyl, 5- 0x0- 1 ,4-diazepan- l -yl, l,4-diazepan- l -yl, 5 ,6-dihydroimidazo[ l ,2-a]pyrazin-7(8H)-yl, 3 - oxo-3 ,4-dihydroquinoxalin- l (2H)—yl, 7,8-dihydro- l hthyridin-6(5H)-yl, 4- oxohexahydropyrrolo[ l ,2-a]pyrazin-2( l H)-yl, 4-oxodihydro- l H-pyrido[ l ,2-a]pyrazin- 2(6H,7H,8H,9H,9aH)-yl, pyrrolidin-l-yl, l, l -dioxido- l ,2,5-thiadiazinanyl, 5,7- dihydro-6H-pyrrolo[3,4-d]pyrimidinyl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, and 2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridinyl, each of which is ally substituted. In some embodiments, the optional substituents are one or two groups independently chosen from halo, lower alkyl optionally substituted with halo, cycloalkyl, and lower alkoxy optionally substituted with halo.
Also provided is at least one chemical entity chosen from compounds of Formula II R1 o ( o Formula II and pharmaceutically able salts and prodrugs thereof, wherein n is chosen from I and 2 and n R1, R2, X, and Y are as described for compounds of Formula I.
In some embodiments, n is 1. In some embodiments, n is 2.
Also provided is a compound chosen from hloromethoxy-phenyl)-pyrimidinecarboxylic acid, 6-(3-Aminochloro-phenyl)-pyrimidinecarboxylic acid, 6-[4-Chloro-3 -(tetrahydro-furanyloxy)-phenyl]-pyrimidinecarboxylic acid, 6-[4-Chloro-3 -(tetrahydro-furanyloxy)-phenyl]-pyrimidinecarboxylic acid pyridin- 3-ylamide, 6-[4-Chloro(2-morpholinyl-ethoxy)-phenyl]-pyrimidinecarboxylic acid n- 3-yl-amide, 6-(3-Chloroisopropyl-phenyl)-pyrimidinecarboxylic acid, 6-(3-F1u0r0rncthy1—phcnyl)—pyrimidinccarboxylic acid, 6-(3-Chlor0isopr0p0xy-phcny1)—pyrirnidinccarboxylic acid, 6-(3-Chloroisopr0p0xy-phcnyl)rncthy1—pyrirnidinccarb0xylic acid, 1u0r0rncthy1—phcnyl)—2-rncthy1—pyrirnidinccarb0xylic acid, 6-(3-Chlorocyclopcntyloxy-phcnyl)-pyrirnidinccarboxylic acid, 6-(3-Chlorotrifluoromcthoxy-phcnyl)-pyrirnidinccarb0xylic acid, 6-(3-F1u0r0isopr0pyl-phcny1)—pyrirnidinccarboxylic acid, 6-(4-(R)—scc-But0xychloro-phcnyl)-pyrirnidinccarb0xylic acid, 6-(4-(S)—scc-Butoxy-3 -ch10ro-phcny1)—pyrirnidinccarboxylic acid, hlorocyclopropoxy-phcnyl)-pyrirnidinccarboxylic acid, 6- [3 -Ch10r0(2,2,2-trifluororncthyl-cthoxy)-phcnyl]-pyrirnidinccarboxylic acid, 4-(3-Ch10r0cyclopropoxy-phcnyl)-pyridinc-Z-carb0xy1ic acid, 6-(4-(R)-scc-Butoxych10ro-phcny1)—pyridinccarb0xylic acid, 6-(4-(S)-scc-Butoxychloro-phcny1)-pyridinccarboxylic acid, 4-(3-Chloroisopropoxy-phcny1)—pyridinc-Z-carboxy1ic acid, 4-(3-Chlorotrifluororncthoxy-phcnyl)-pyridinccarboxylic acid, 6-(3-Chlorocyc10but0xy-phcnyl)—pyrirnidinccarb0xylic acid, 6- [3 -Ch10r0(2-pipcridiny1-cth0xy)-phcnyl]-pyrirnidinccarb0xylic acid, 6-Quino1iny1-pyrirnidinccarboxy1ic acid, 6-(8-Ch10r0-chr0rnanyl)—pyrirnidinccarboxylic acid, 6-(7-Chlor0-bcnzofiarany1)-pyrirnidinccarboxy1ic acid, 6-[3-Ch10r0(pyrr01idinyloxy)-phcnyl]-pyrirnidinccarb0xylic acid, hlor0rncthy1—1,2,3 ,4-tctrahydr0quinoliny1)pyrirnidinccarb0xylic acid, 6-(8-ch10r0quinolinyl)pyrirnidinccarboxylatc, N—[6-(3-ch10rocyclopropoxyphcnyl)pyrirnidinyl]bcnzcncsulfonarnidc, N—[6-(3 -chlorocyclopropoxyphcnyl)pyrirnidiny1]fluorobcnzcncsu1fonarnidc, N—[6-(3-ch10r0cyclopr0p0xyphcnyl)pyrirnidinyl](trifluor0rncthoxy)bcnzcnc sulfonarnidc, N—[6-(3 -chlorocyclopropoxyphcnyl)pyrirnidiny1] -3 -(trifluororncthoxy)bcnzcnc sulfonarnidc, N—[6-(3 -chlorocyclopropoxyphcnyl)pyrirnidiny1]fluorobcnzcncsu1fonarnidc, 3-chlorocyclopropoxyphcnyl)pyrirnidinyl]cyclopropancsulfonamidc, 6-(8-chlor0- 1 ,2,3 ,4-tctrahydr0quino1iny1)pyrirnidinccarb0xy1atc, 6-(3-chlorocyclopropoxyphcnyl)rncthy1pyrimidinccarboxylatc, 6- {3 -ch10r0[2-(rn0rpholiny1)cthoxy]phcnyl}pyrimidinecarboxy1atc, 6-[3-chloro(cyclopropylmcthoxy)phcnyl]pyrirnidinccarboxy1atc, 6-[3-ch10ro(0xctan-3 -y10xy)phcny1]pyrirnidinccarboxylatc, 4-(3-ch10r0cyclopr0poxyphcnyl)-5H,7H-fi1r0[3,4-d]pyrirnidinonc, 6-(3-chlorocyclopropoxyphcnyl)(hydroxymcthyl)pyrirnidinccarboxy1ic acid, 4-(3-chlor0cyclopr0poxyphcny1)-5H,6H,8H-pyran0[3,4-d]pyrirnidinonc, [(2R,3S,4S,5R)—3,4,5,6-tctrahydroxyoxany1]rncthyl 6-(3-ch10ro cyclopropoxyphcnyl)pyrirnidinccarboxy1atc, 6-(3-ch10r0 {[1-(rn0rph01inyl)propany1]oxy}phenyl)pyrirnidinccarb0xy1ic acid, 6-[3-ch10r0(cyclopropoxymcthyl)phcnyl]pyrimidinecarboxy1ic acid, 6-[3-chlor0(cyclopropylrncthyl)phcnyl]pyrirnidinccarb0xy1ic acid, 6-[3-ch10r0(cyc10propylsulfanyl)phcnyl]pyrirnidinccarboxylic acid, 6-[3-chlor0(cyclopropancsulfiny1)phcnyl]pyrimidinecarboxylic acid, 6-[3-ch10r0(cyclopr0pancsulfonyl)phcnyl]pyrimidinecarboxylic acid, 6- {3-chlor0[cyclopropyl(hydroxy)rncthyl]phcnyl}pyrimidinccarboxylic acid, 6-[3-ch10r0(1 -cyc10prop0xycthyl)phcnyl]pyrirnidinccarboxylic acid, 6-(3-chlor0cyc10pr0panccarbonylphcnyl)pyrirnidinccarboxylic acid, 6-(3-ch10r0cyclopropylphcnyl)pyrirnidinccarb0xy1ic acid, 6-[4-(aziridiny1rncthy1)—3 -chlor0phcnyl]pyrimidinecarboxylic acid, 6- 0ro[(dimcthylamino)mcthyl]phcnyl}pyrimidinecarboxylic acid h10r0(cyclopropylarnino)phcnyl]pyrirnidinccarboxylic acid, 6- {3-chloro[cyc10pr0py1(rncthyl)amino]phcnyl}pyrimidinecarboxylic acid, 6- {3-chloro[(cyclopropylamino)rncthyl]phcnyl}pyrimidinecarboxylic acid, 6-(3 -chlor0 {[cyc10pr0py1(rncthy1)arnino]methyl}phenyl)pyrirnidinccarb0xylic acid, 6-(7-chlorocyclopropyl-2,3-dihydro-1H-isoindol-5 -y1)pyrirnidinccarboxylic acid, 6-[3-chloro(furany1)phcnyl]pyrirnidinccarb0xy1ic acid, 6- [3 -ch10r0(1-mcthoxycyclopropyl)phcnyl]pyrirnidinccarboxylic acid, 6-(2,3-dihydr0-1 zodioxinyl)pyrirnidinccarb0xy1ic acid, 6-(7-ch10r0rncthy1— 1 ,3 -bcnzoxazoly1)pyrimidinccarboxylic acid, h10r00X0-2,3-dihydr0-1 ,3-bcnzoxazol-5 -y1)pyrirnidinccarb0xy1ic acid, 6-(7-ch10r0-3 -rncthyl0X0-2,3 -dihydr0-1 ,3-bcnz0xaz01—5 -y1)pyrirnidinccarb0xy1ic acid, 6-(7-chlorocyclopropy1- 1 ,3-bcnzoxazol-5 -y1)pyrirnidinccarboxy1ic acid, 6-{8-chlor0irnidaz0[1,2-a]pyridiny1}pyrimidinecarboxylic acid, 6-(4-ch10r0-1,3-bcnzoxazo1y1)pyrirnidinccarboxylic acid, 6-(quino1iny1)pyrirnidinccarboxylic acid, 6-{pyraz010[1,5-a]pyridiny1}pyrimidinecarboxylic acid, 6-(4-chlorocyclopropoxyphcnyl)pyrirnidinccarboxylic acid, 6-(4-ch10r0rncth0xyphcnyl)pyrirnidinccarboxylic acid, 6-[4-ch10r0(pr0pany10xy)phcnyl]pyrirnidinccarb0xylic acid, 6-[4-chloro(2-mcthylpropoxy)phcnyl]pyrimidinecarboxylic acid, h10r0(trifluororncthoxy)phcnyl]pyrimidinecarboxylic acid, 6- {4-chlor0-3 -[(1,1,1-triflu0ropropanyl)0xy]phcnyl}pyrimidinecarboxylic acid, 6-(bcnzo[d][1,3]di0X01—5-y1)pyrirnidinccarboxylic acid, 6-(2,2-difluorobcnzo[d][1,3]di0x01—5-y1)pyrirnidinccarboxylic acid, 6-(2,3-dihydrobcnzo[b][1,4]dioxiny1)pyrirnidinccarb0xy1ic acid, 6-(7-chlorobcnzo[b]thiophcny1)pyrirnidinccarboxylic acid, 6-(7-chlorobcnzo[d]thiaz01—5-y1)pyrirnidinccarboxylic acid, 6-(7-chlorobcnzo[d]oxazoly1)pyrirnidinccarboxylic acid, 6-(7-chlorobcnzo[c][1,2,5]oxadiazoly1)pyrirnidinccarboxy1ic acid, 6-(7-ch10r0-2,3 ,3a,7a-tctrahydrobcnzofuran-S-y1)pyrirnidinccarboxylic acid, 6-(7-ch10r0-3a,7a-dihydr0-1H-indoly1)pyrirnidinccarboxylic acid, h10r0-1 -rncthy1—3 a,7a-dihydr0- 1 zol-S -y1)pyrirnidinccarb0xy1ic acid, 6-(8-chloroquinazo1iny1)pyrirnidinccarb0xylic acid, hloroquinazo1iny1)pyrirnidinccarb0xylic acid, 6-(8-ch10r0quin0xaliny1)pyrirnidinccarboxylic acid, 6-(8-ch10r0-1 ,2,3 ,4-tctrahydr0quinoliny1)pyrimidinccarboxylic acid, 6-(7-ch10ro- 1 H-bcnzo [d]imidazol-S -y1)pyrirnidinccarb0xy1ic acid, 6-(3-ch10r0(1-rncthylcyc10pr0py1)phcnyl)pyrimidinccarboxylic acid, 6-(3-ch10r0(1-(trifluor0mcthyl)cyc10pr0py1)phcnyl)pyrirnidinccarboxylic acid, 6-(3-ch10r0(3 -rncthyloxctan-3 -y1)phcny1)pyrirnidinccarb0xy1ic acid, 6-(3 -ch10r0(pyrr01idiny1)phcnyl)pyrirnidinccarb0xy1ic acid, 6-(3-ch10ro(pyrrolidiny1)phcnyl)pyrirnidinccarb0xylic acid, 6-(3-ch10ro(pyrro1idiny1)phcnyl)pyrirnidinccarb0xylic acid, 6-(3-ch10r0(1H-irnidazo1y1)phcnyl)pyrirnidinccarboxylic acid, 6-(3-chloro(l H-pyrrolyl)phenyl)pyrirnidinecarboxylic acid, 6-(4-tert-butyl-3 -chlorophenyl)pyrirnidinecarboxylic acid, and 7-chlorocyclopropoxy-5H-chrorneno[4,3-d]pyrirnidinecarboxylic acid. or a pharmaceutically acceptable salt or prodrug thereof.
Also provided is a nd chosen from 6-[3-chloro(rnethylsulfanyl)phenyl]pyrimidinecarboxylic acid, 6-[3-chloro(rnethylsulfinyl)phenyl]pyrirnidinecarboxylic acid, 6-[3-chloro(methylsulfonyl)phenyl]pyrimidinecarboxylic acid, 6- {3-chloro[cyclopropyl(hydroxy)rnethyl]phenyl}pyrirnidinecarboxylic acid, 6-(3-chlorocyclopropanecarbonylphenyl)pyrirnidinecarboxylic acid, 6-[3-chloro(methoxyrnethyl)phenyl]pyrimidinecarboxylic acid, hloro(l -rnethoxyethyl)phenyl]pyrirnidinecarboxylic acid, 6- {3-chloro[(dimethylamino)rnethyl]phenyl}pyrimidinecarboxylic acid, 6-[3-chloro(cyclopropylarnino)phenyl]pyrirnidinecarboxylic acid, 6- {3-chloro[cyclopropyl(rnethyl)amino]phenyl}pyrimidinecarboxylic acid, 6-(3 -chloro(pyrrolidin- l enyl)pyrirnidinecarboxylic acid, 6-(7-chlorornethyl- l ,3 -benzoxazolyl)pyrirnidinecarboxylic acid, 6-(8-chloroquinoxalinyl)pyrirnidinecarboxylic acid, 6-(7-chloro-2,3 ro- l -benzofuran-5 -yl)pyrimidinecarboxylic acid, 6-(7-chlorocyclopropyl- l ,3-benzoxazol-5 -yl)pyrirnidinecarboxylic acid, 6-(4-chlorornethyl- l ,3 -benzoxazolyl)pyrirnidinecarboxylic acid, 6-(7-chloro-3 -rnethyloxo-2,3 -dihydro- l ,3 -benzoxazol-5 -yl)pyrirnidinecarboxylic acid, 6-(2H- l ,3-benzodioxolyl)pyrimidinecarboxylic acid, 4-(3 ,4-dichlorophenyl)rnethylpyridinecarboxylic acid, 6-(3-chloro {[l-(rnorpholinyl)propanyl]oxy}phenyl)pyrirnidinecarboxylic acid, 6-[3-chloro(cyclopropoxymethyl)phenyl]pyrimidinecarboxylic acid, hloro(cyclopropylrnethyl)phenyl]pyrirnidinecarboxylic acid, 6-[3-chloro(l -cyclopropoxyethyl)phenyl]pyrirnidinecarboxylic acid, 6-(3-chlorocyclopropylphenyl)pyrirnidinecarboxylic acid, 6- [4-(aziridin- l -ylmethyl)—3 -chlorophenyl]pyrimidinecarboxylic acid, 6- {3-chloro[(cyclopropylamino)rnethyl]phenyl}pyrimidinecarboxylic acid, 6-(3 -chloro { [cyclopropyl(rnethyl)amino]rnethyl}phenyl)pyrirnidinecarboxylic acid, 6-(7-chlorocyclopropyl-2,3-dihydro-1H-isoindol-5 -y1)pyrirnidinccarboxylic acid, 6-[3-chloro(furany1)phcnyl]pyrirnidinccarb0xy1ic acid, 6- [3 -ch10r0(1-mcthoxycyclopropyl)phcnyl]pyrirnidinccarboxylic acid, 6-(2,3-dihydr0-1 zodioxinyl)pyrirnidinccarb0xy1ic acid, 6-(7-ch10r00X0-2,3-dihydr0-1 ,3-bcnzoxazol-5 -y1)pyrirnidinccarb0xy1ic acid, 6-{8-chlor0irnidaz0[1,2-a]pyridiny1}pyrimidinecarboxylic acid, 6-(4-ch10r0-1,3-bcnzoxazo1y1)pyrirnidinccarboxylic acid, 6-(quino1iny1)pyrirnidinccarboxylic acid, 6-{pyraz010[1,5-a]pyridiny1}pyrimidinecarboxylic acid, 6-(4-chlorocyclopropoxyphcnyl)pyrirnidinccarboxylic acid, 6-(4-ch10r0rncth0xyphcnyl)pyrirnidinccarboxylic acid, 6-[4-ch10r0(pr0pany10xy)phcnyl]pyrirnidinccarb0xylic acid, 6-[4-chloro(2-mcthylpropoxy)phcnyl]pyrimidinecarboxylic acid, h10r0(trifluororncthoxy)phcnyl]pyrimidinecarboxylic acid, 6- {4-chlor0-3 -[(1,1,1-triflu0ropropanyl)0xy]phcnyl}pyrimidinecarboxylic acid, 6-(2,2-difluorobcnzo[d][1,3]di0x01—5-y1)pyrirnidinccarboxylic acid, 6-(2,3-dihydrobcnzo[b][1,4]dioxiny1)pyrirnidinccarb0xy1ic acid, 6-(7-chlorobcnzo[b]thiophcny1)pyrirnidinccarboxylic acid, 6-(7-chlorobcnzo[d]thiaz01—5-y1)pyrirnidinccarboxylic acid, 6-(7-chlorobcnzo[d]oxazoly1)pyrirnidinccarboxylic acid, 6-(7-chlorobcnzo[c][1,2,5]oxadiazoly1)pyrirnidinccarboxy1ic acid, 6-(7-ch10r0-3a,7a-dihydr0-1H-indoly1)pyrirnidinccarboxylic acid, 6-(7-ch10r0-1 -rncthy1—3 a,7a-dihydr0- 1 H-indazol-S -y1)pyrirnidinccarb0xy1ic acid, 6-(8-chloroquinazo1iny1)pyrirnidinccarb0xylic acid, hloroquinazo1iny1)pyrirnidinccarb0xylic acid, 6-(7-ch10ro- 1 H-bcnzo [d]imidazol-S rirnidinccarb0xy1ic acid, 6-(3-ch10r0(1-rncthylcyc10pr0py1)phcnyl)pyrimidinccarboxylic acid, 6-(3-ch10r0(1-(trifluor0mcthyl)cyc10pr0py1)phcnyl)pyrirnidinccarboxylic acid, 6-(3-ch10r0(3 -rncthyloxctan-3 -y1)phcny1)pyrirnidinccarb0xy1ic acid, 6-(3-ch10ro(pyrro1idiny1)phcnyl)pyrirnidinccarb0xylic acid, 6-(3-ch10r0(1H-irnidazo1y1)phcnyl)pyrirnidinccarboxylic acid, 6-(3-ch10r0(1 H-pyrro1y1)phcnyl)pyrirnidinccarb0xy1ic acid, 6-(4-tcrt-butyl-3 -chlor0phcnyl)pyrirnidinccarboxylic acid, and 7-chlorocyclopropoxy-5H-chromeno[4,3-d]pyrimidinecarboxylic acid, or a pharmaceutically acceptable salt or prodrug thereof.
Methods for obtaining the al entitites described herein will be nt to those of ordinary skill in the art, suitable procedures being described, for example, in examples below, and in the references cited herein.
Provided is a method of ting the catalytic activity of KMO, comprising contacting said KMO with an effective amount of at least one chemical entity described herein.
Also provided is a method of ng a condition or disorder ed by KMO activity in a subject in need of such a treatment, comprising administering to the subej ct a therapeutically effective amount of at least one chemical entity described herein.
Also provided is a method of treating a neurodegenerative pathology mediated by KMO activity in a subject in need of such a treatment, comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein.
Also ed is a method for treating disorders ed by (or at least in part by) the presence 3-OH-KYN, QUIN and/or KYNA. Also provided is a method of treating a degenerative or inflammatory condition in which an increased synthesis in the brain of QUIN, 3-OH-KYN or increased release of GLU are involved and which may cause neuronal damage.
] Such diseases include, for example, Huntington's disease and other polyglutamine disorders such as erebellar ataxias neurodegenerative diseases, psychiatric of neurological es or disorders, Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis, feld-Jacob disease, trauma-induced egeneration, high-pressure neurological syndrome, dystonia, ontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia, ischemic disorders including stroke (focal ia), hypoxia, multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal cord, Dementia such as senile dementia and AIDS-dementia complex, AIDS-induced encephalopathy, other infection related encephalopathy, viral or bacterial meningitis, infectious diseases caused by viral, bacterial and other parasites, for example, general central nervous system (CNS) ions such as viral, bacterial or parasites, for example, poliomyelitis, Lyme e (Borrelia burgdorferi infection) septic shock, and malaria, cancers, cancers with cerebral localization, c encephalopathy, systemic lupus, analgesia and opiate withdrawal symptoms, feeding behavior, psychiatric disorders, such as insomnia, sion, schizophrenia, severe deficit in working , severe deficit in long term memory storage, decrease in cognition, severe deficit in attention, severe deficit in executive filnctioning, sloweness in information processing, slowness in neural activity, anxiety, generalized anxiety disorders, panic anxiety, obsessive compulsive ers, social , performance anxiety, post-traumatic stress disorder, acute stress on, adjustment reaction, separation anxiety disorder, alcohol withdrawal anxiety, depressive disorders, disorders of the developing or aged brain, diabetes, and complications thereof, Tourette's syndrome, Fragile X syndrome, autism spectrum disorders, disorders that cause severe and pervasive impairment in thinking feeling, language and the ability to relate to others, mood disorders, psychological disorders characterized by abnormalities of emotional state, such as t limitation, bipolar disorder, unipolar depression, major depression, ondougenous depression, involutional depression, reactive depression, psychotic depression, depression caused by underlying l conditions, depressive disorders, cyclothymic disorders, dysthymic disorders, mood disorders due to general medical condition, mood disorders not ise specified and nce-induced mood disorders. Such disease also include, for example, Acute necrotizing Pancreatitis, AIDS (disease), Analgesia, Aseptic meningitis, Brain disease, for example, Gilles de la Tourette syndrome, Asperger syndrome, Rett syndrome, pervasive developmental disorders, aging-related Brain disease, and developmental Brain disease, burnout syndrome, carbon monoxide poisoning, cardiac arrest or insufficiency and hemorrhagic shock (global brain ischemia), cataract formation and aging of the eye, Central nervous system e, Cerebrovascular disease, chronic fatigue syndrome, c Stress, Cognitive disorders, convulsive ers, such as variants of Grand mal and petit mal epilepsy and l Complex Epilepsy, Diabetes mellitus, Disease of the nervous system (e.g., dyskinesia, L-DOPA induced movement disorders, drug addiction, pain and cataract), Drug dependence, Drug withdrawal, feeding disorders, Guillain Barr me and other neurophaties, Hepatic encephalopathy, Immune disease, immunitary ers and therapeutic treatment aimed at modifying ical responses (for instance strations of interferons or interleukins), Inflammation (systemic inflammatory response syndrome), inflammatory disorders of the central and/or eral nervous system, Injury (trauma, polytrauma), Mental and behavioral disorders, Metabolic disease, pain disease, or disorder selected from a group of inflammatory pain, neurophathic pain or migraine, allodynia, hyperalgesis pain, phantom pain, neurophatic pain related to diabetic neuropathy, le organ failure, near drowning, Necrosis, sms of the brain, stic disorders including lymphomas and other malignant blood disorders, s system disease (high-pressure neurol. Syndrome, ion), nicotine addiction and other addictive disorders including alcoholism, cannabis, benzodiazepine, barbiturate, ne and cocaine dependence, change in appetite, sleep disorders, changes in sleep patem, lack of energy, fatigue, low self steem, self-reproach inappropriate guilt, frequent thoughts of death or suicide, plans or attemps to commit suicide, feelings of hopelessness and worthlessness, psychomotor agitation or retardation, diminished capacity for thinking, concentration, or decisiveness, as a rotective , Pain, Post-traumatic stress disorder, Sepsis, Spinal cord disease, Spinocerebellar ataxia, ic lupus erythematosis, traumatic damage to the brain and spinal cord, and tremor syndromes and different movement disorders (diskynesia). Poor balance, brakykinesia, rigidity, tremor, change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling, ia, confussion, fear, sexual disfunction, language impairment, ment in decision making, violent outbursts, aggression, hallucination, , impairment in abstract thinking.
Such diseases include, for example, cardiovascular diseases, which refers to diseases and disorders of the heart and circulatory system. These diseases are often associated with dyslipoproteinemias and/or dyslipidemias. vascular diseases include but are not limited to cardiomegaly, atherosclerosis, myocardial infarction, and congestive heart failure, coronary heart disease, hypertension and nsion.
Other such diseases include hyperproliferative diseases of benign or malignant behaviour, in which cells of various tissues and organs exhibit aberrant patterns of growth, proliferation, migration, signaling, senescence, and death. Generally hyperpoliferative disease refers to diseases and disorders associated with, the uncontrolled eration of cells, including but not d to uncontrolled growth of organ and tissue cells resulting in s and benign tumors. Hyperproliferative disorders associated with endothelial cells can result in diseases of angiogenesis such as angiomas, endometriosis, obesity, Age-related Macular Degeneration and various retinopaties, as well as the proliferation of ECs and smooth muscle cells that cause restenosis as a consequence of stenting in the treatment of atherosclerosis. Hyperproliferative disorders involving fibroblasts (i.e., fibrogenesis) include but are not limited to disorers of excessive scaring (i.e., fibrosis) such as Age-related Macular Degeneration, cardiac remodeling and failure associated with myocardial infarction, excessive wound healing such as commonly occurs as a consequence of y or injury, keloids, and fibroid tumors and stenting.
Additional diseases include transplant rejection (suppression of T-cells) and graft vs host disease, c kidney disease, systemic inflammatory disorders, brain inflammatory disorders including malaria and African trypanosomiasis, stroke, and pneumococcal meningitis.
] Also provided are methods of treatment in which at least one chemical entity described herein is the only active agent given to the subject and also includes methods of treatment in which at least one chemical entity described herein is given to the t in combination with one or more additional active agents.
In general, the chemical entities described herein will be stered in a therapeutically effective amount by any of the accepted modes of stration for agents that serve r utilities. The actual amount of the compound, i.e., the active ingredient, will depend upon numerous s such as the severity ofthe disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well know to the skilled artisan. The drug can be administered at least once a day, such as once or twice a day.
In some embodiments, the chemical entities described herein are administered as a pharmaceutical composition. Accordingly, provided are pharmaceutical compositions comprising at least one chemical entity described , together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to render them suitable for stration to the animal being treated. The vehicle can be inert or it can possess pharmaceutical benefits. The amount of vehicle ed in conjunction with the al entity is sufficient to provide a practical quantity of al for administration per unit dose of the chemical entity.
Exemplary ceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered anth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerine, sorbitol, ol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
Optional active agents may be included in a ceutical composition, which do not substantially interfere with the actiVity of the chemical entity bed herein.
Effective concentrations of at least one chemical entity described herein are mixed with a suitable pharmaceutically acceptable vehicle. In instances in which the chemical entity exhibits insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as ylsulfoxide (DMSO), using surfactants, such as TWEEN, or ution in aqueous sodium bicarbonate.
Upon mixing or addition of a chemical entity described herein, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, ing the intended mode of administration and the solubility of the chemical entity in the chosen vehicle. The effective tration sufficient for ameliorating the symptoms of the disease treated may be cally determined.
Chemical entities described herein may be administered orally, topically, parenterally, intravenously, by intramuscular injection, by inhalation or spray, gually, transdermally, Via buccal administration, ly, as an ophthalmic solution, or by other means, in dosage unit ations.
Pharmaceutical compositions may be formulated for oral use, such as for example, s, troches, lozenges, aqueous or oily suspensions, dispersible s or granules, emulsions, hard or soft capsules, or syrups or elixirs. Pharmaceutical itions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, such as ning agents, ng agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. In some embodiments, oral pharmaceutical compositions n from 0.1 to 99% of at least one chemical entity described herein. In some embodiments, oral pharmaceutical compositions contain at least 5% (weight %) of at least one chemical entity described herein. Some embodiments n from 25% to 50% or from 5% to 75 % of at least one chemical entity described herein.
Orally administered pharmaceutical compositions also include liquid solutions, emulsions, sions, powders, granules, elixirs, tinctures, syrups, and the like. The pharmaceutically acceptable carriers suitable for preparation of such compositions are well known in the art. Oral pharmaceutical compositions may contain preservatives, flavoring agents, sweetening agents, such as e or saccharin, taste- masking agents, and coloring agents.
Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, ol, propylene glycol, polyethylene , liquid sucrose, sorbitol and water. Syrups and elixirs may be formulated with sweetening agents, for example ol, propylene glycol, sorbitol or e. Such pharmaceutical compositions may also n a demulcent.
Chemical entities described herein can be orated into oral liquid preparations such as aqueous or oily suspensions, solutions, ons, syrups, or elixirs, for example. er, pharmaceutical compositions containing these chemical entities can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional ves, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e. g., lecithin, sorbitan monsoleate, or acacia), non-aqueous vehicles, which can include edible oils (e. g., almond oil, fractionated coconut oil, silyl esters, ene glycol and ethyl alcohol), and preservatives (e. g., methyl or propyl p-hydroxybenzoate and sorbic acid).
For a suspension, typical suspending agents include methylcellulose, sodium carboxymethyl cellulose, Avicel RC-59l, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. ] s suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents; may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or sation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for e polyethylene sorbitan substitute. The s suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate.
Oily suspensions may be ated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or t oil, or in a mineral oil such as liquid paraffin. The oily suspensions may n a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to e palatable oral preparations.
These pharmaceutical itions may be ved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a ble oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be lly-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
Dispersible powders and granules suitable for ation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or g agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Tablets typically comprise conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; s such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, c acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components often depends on secondary considerations like taste, cost, and shelf stability.
Such pharmaceutical compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the chemical entity is released in the gastrointestinal tract in the vicinity of the d topical application, or at various times to extend the desired action. Such dosage forms typically e, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for e, calcium carbonate, calcium phosphate or , or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Pharmaceutical compositions may be in the form of a e able s or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile inj e preparation may also be sterile inj ectable solution or suspension in a non-toxic parentally able e, for example as a solution in l,3-butanediol. Among the acceptable es that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, e, fixed oils are conventionally employed as a solvent or suspending . For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In on, fatty acids such as oleic acid can be useful in the preparation of inj ectables.
Chemical entities described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous ions, intravenous, intramuscular, intrathecal injection or infiasion techniques. Chemical entities described herein, depending on the vehicle and concentration used, can either be ded or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many ceutical compositions for parenteral administration the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for eral administration is chosen from propylene glycol, ethyl , pyrrolidone, ethanol, and sesame oil.
Chemical entites described herein may also be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable ritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
Chemical entities described herein may be formulated for local or topical ation, such as for topical application to the skin and mucous nes, such as in the eye, in the form of gels, creams, and lotions and for ation to the eye. Topical pharmaceutical compositions may be in any form including, for example, ons, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, and the like.
Such solutions may be formulated as 0.01% -10% isotonic ons, pH 5- 7, with appropriate salts. Chemical entities described herein may also be formulated for transdermal administration as a transdermal patch.
Topical pharmaceutical compositions comprising at least one chemical entity described herein can be admixed with a y of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
Other materials suitable for use in l carriers include, for example, emollients, solvents, humectants, thickeners and s. Examples of each of these types of als, which can be used singly or as mixtures of one or more materials, are as follows: ] Representative emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-l,2-diol, butane-l,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecanol, isocetyl alcohol, cetyl palmitate, ylpolysiloxane, di-n-butyl te, iso-propyl myristate, isopropyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, s oil, castor oil, acetylated lanolin alcohols, petroleum, l oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl , and myristyl myristate; propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and s oxide; solvents, such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol hyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofilran; humectants, such as glycerin, sorbitol, sodium 2-pyrrolidonecarboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium tes, trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, filmed silica, carboxyvinyl polymer, sodium carboxymethyl ose, and ethylene glycol monostearate.
The chemical entities described herein may also be topically administered in the form of me delivery s, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or atidylcholines.
Other pharmaceutical compositions useful for ing systemic delivery of the chemical entity include gual, buccal and nasal dosage forms. Such pharmaceutical compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline ose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
Pharmaceutical compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or orofluoromethane).
The pharmaceutical compositions may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules that function in ent ways to enhance or be independent of therapeutic s of the chemical entities described herein. Particular classes of ty enhancers include skin penetration enhancers and absorption enhancers.
Pharmaceutical compositions may also contain additional active agents that can be chosen from a wide variety of molecules, which can function in different ways to enhance the eutic effects of at least one chemical entity described herein. These optional other active agents, when present, are typically employed in the pharmaceutical compositions at a level ranging from 0.01% to 15%. Some embodiments contain from 0.1% to 10% by weight of the composition. Other embodiments contain from 0.5% to 5% by weight of the composition.
Also provided are packaged ceutical compositions. Such packaged compositions include a pharmaceutical ition comprising at least one chemical entity described herein, and instructions for using the composition to treat a subject (typically a human patient). In some embodiments, the instructions are for using the pharmaceutical composition to treat a subject suffering a condition or disorder mediated by nine 3-mono-oxygenase activity. The packaged pharmaceutical composition can include providing prescribing information; for example, to a t or health care provider, or as a label in a packaged pharmaceutical composition. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical composition.
In all of the foregoing the chemical entities can be administered alone, as es, or in ation with other active agents.
The methods bed herein include methods for treating Huntington's disease, including treating memory and/or cognitive impairment associated with Huntington's disease, comprising administering to a subject, simultaneously or sequentially, at least one chemical entity described herein and one or more onal agents used in the treatment of Huntington's disease such as, but not limited to, Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, and idone. In methods using simultaneous administration, the agents can be t in a combined ition or can be administered separately. As a result, also provided are pharmaceutical compositions comprising at least one chemical entity described herein and one or more additional pharmaceutical agents used in the treatment of Huntington's disease such as, but not limited to, Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
Similarly, also provided arepackaged pharmaceutical compositions containing a pharmaceutical composition comprising at least one chemical entity described herein, and another composition comprising one or more additional pharmaceutical agents used in the treatment of Huntington's disease such as, but not limited to, Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine, ridol, Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
] Also provided are methods for treating Parkinson's disease, including treating memory and/or cognitive impairment associated with Parkinson's disease, comprising administering to a subject, simultaneously or sequentially, at least one chemical entity described herein and one or more additional agents used in the ent of Parkinson's disease such as, but not d to, Levodopa, Parlodel, , Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin. In methods using simultaneous administration, the agents can be present in a combined composition or can be stered separately. Also provided are pharmaceutical compositions comprising at least one chemical entity described herein, and one or more additional pharmaceutical agents used in the treatment of Parkinson's disease, such as, but not limited to, Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin. Also ed are packaged pharmaceutical compositions containing a pharmaceutical composition comprising at least one chemical entity described herein, and another composition comprising one or more additional ceutical agents gent used in the treatment of Parkinson's e such as, but not limited to, Levodopa, el, Permax, x, Tasmar, Contan, Kemadin, Artane, and Cogentin.
Also provided are methods for treating memory and/or cognitive impairment associated with Alzheimer's disease, comprising administering to a subject, simultaneously or sequentially, at least one chemical entity described herein and one or more onal agents used in the ent of Alzheimer's e such as, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, en and Cliquinol. In methods using simultaneous administration, the agents can be present in a combined ition or can be administered separately. Also provided are pharmaceutical compositions comprising at least one chemical entity described herein, and one or more onal pharmaceutical agents used in the treatment of Alzheimer's e such as, but not limited to, Reminyl, Cognex, Aricept, , Akatinol, Neotropin, Eldepryl, en and Cliquinol. Similarly, also ed are packaged pharmaceutical compositions containing a pharmaceutical composition comprising at least one chemical entity described herein, and another composition comprising one or more additional pharmaceutical agents used in the treatment of Alzheimer's disease such as, but not limited to Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol.
Also provided are methods for treating memory and/or cognitive impairment associated with dementia or ive impairment comprising administering to a subject, simultaneously or sequentially, at least one chemical entity and one or more additional agents used in the treatment of dementia such as, but not limited to, Thioridazine, Haloperidol, Risperidone, Cognex, Aricept, and Exelon. In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. Also provided are pharmaceutical compositions comprising at least one chemical entity described , and one or more additional ceutical agents used in the treatment of dementia such as, but not limited to, Thioridazine, Haloperidol, Risperidone, Cognex, t, and Exelon. Also provided are packaged pharmaceutical compositions containing a pharmaceutical composition comprising at least one chemical entity described herein, and another composition comprising one or more additional pharmaceutical agents used in the treatment of dementia such as, but not limited to, Thioridazine, ridol, Risperidone, Cognex, Aricept, and Exelon.
] Also provided are methods for treating memory and/or cognitive impairment associated with epilepsy comprising administering to a subject, simultaneously or sequentially, at least one chemical entity bed herein and one or more onal agents used in the treatment of sy such as, but not limited to, Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin, tin, Barbita, Solfeton, and Felbatol. In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. Also provided are pharmaceutical compositions sing at least one chemical entity described herein, and one or more additional pharmaceutical agents used in the treatment of epilepsy such as, but not limited to, in, Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin, Barbita, Solfeton, and Felbatol. Also provided are packaged pharmaceutical compositions containing a pharmaceutical composition sing at least one chemical entity described herein, and another composition sing one or more onal pharmaceutical agents used in the treatment of epilepsy such as, but not limited to, Dilantin, Luminol, ol, Depakote, Depakene, in, tin, Barbita, Solfeton, and Felbatol.
Also provided are methods for treating memory and/or cognitive impairment associated with multiple sclerosis comprising administering to a subject, aneously or tially, at least one chemical entity described herein and one or more additional agents used in the treatment of multiple sclerosis such as, but not d to, Detrol, an XL, OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone. In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. Also ed are pharmaceutical compositions comprising at least one chemical entity described herein, and one or more additional pharmaceutical agents used in the treatment of multiple sis such as, but not limited to, Detrol, Ditropan XL, OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone. Also provided are packaged pharmaceutical compositions containing a pharmaceutical composition comprising at least one chemical entity described , and another composition comprising one or more additional pharmaceutical agents used in the treatment of multiple sclerosis such as, but not limited to, Detrol, Ditropan XL, tin, Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone.
When used in combination with one or more additional pharmaceutical agent or agents, the described herein may be administered prior to, concurrently with, or following administration of the additional pharmaceutical agent or agents.
The dosages of the nds described herein depend upon a variety of factors including the particular me to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the cy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.
The chemical entities described herein are typically administered at dosage levels and in a manner customary for KMO inhibitors. For example, the chemical entities can be administered, in single or multiple doses, by oral administration at a dosage level of generally 0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, such as 01-70 mg/kg/day, for example, 0.5-10 mg/kg/day. Unit dosage forms can contain generally 0.01-1000 mg of at least one chemical entity described herein, for example, 01-50 mg of at least one chemical entity described herein. For intravenous administration, the compounds can be administered, in single or multiple dosages, at a dosage level of, for example, 0.001-50 mg/kg/day, such as 0.001-10 mg/kg/day, for example, 0.0l-l mg/kg/day. Unit dosage forms can contain, for e, 01-10 mg of at least one chemical entity described herein.
A d form of a chemical entity described herein can be used as a diagnostic for fying and/or obtaining compounds that have the function of modulating an activity ofKMO as described herein. The chemical entities described herein may additionally be used for validating, optimizing, and rdizing bioassays.
By ed" herein is meant that the compound is either directly or ctly labeled with a label which provides a detectable , e. g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the specific binding members, the mentary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above. The label can directly or indirectly provide a detectable signal.
In carrying out the procedures of the methods described herein, it is of course to be understood that reference to particular buffers, media, ts, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to tute one buffer system or e medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient dge of such s and methodologies so as to be able, without undue experimentation, to make such tutions as will optimally serve their es in using the methods and procedures disclosed herein.
EXAMPLES The chemical entities, compositions, and methods described herein are further illustrated by the following non-limiting examples.
As used herein, the following abbreviations have the following meanings.
If an abbreviation is not defined, it has its generally accepted meaning.
CDI = carbonyldiimidazole DCM = romethane DME = dimethyl ether DMEM = Dulbecco's modified Eagle's medium DMF = N,N—dimethylformamide DMSO = dimethylsulfoxide l = l -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride EtOH = ethanol EtzO = diethylether EtOAc = ethyl acetate g = gram hr = hour hrs = hours HOBt = l-Hydroxybenzotriazol LiHMDS = lithium hexamethyl-disilazide LC/MS = liquid chomatography / mass spectrometry mg = milligram min = minutes mL = milliliter mmol = millimoles mM = olar ng = nanogram nm = nanometer nM = nanomolar PBS = ate buffered saline rt = room temperature TBME = t—butyl methyl ether THF = tetrahydrofuran TMOF = trimethylorthoformate uL = microliter uM = micromolar 1g/1ml = 1 vol Experimental Commercially ble reagents and solvents (HPLC grade) were used without further ation.
Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60 F254 (Merck) plates and visualized using UV light. Microwave reactions were carried out using CEM focussed microwaves.
Analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu 2010, systems using e phase Atlantis dC18 columns (5 um, 2.1 X 50 mm), gradient -100% B (A: water/ 0.1% formic acid, B= acetonitrile/ 0.1% formic acid) over 3 min, injection volume 3 ul, flow = 1.0 ml/min. UV spectra were recorded at 215 nm using a Waters 2487 dual wavelength UV detector or the Shimadzu 2010 . Mass a were obtained over the range m/z 150 to 850 at a ng rate of 2 scans per second using Waters ZMD and over m/z 100 to 1000 at a sampling rate of 2Hz using Electrospray ionisation, by a zu 2010 LC-MS system or analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu 2010, systems using reverse phase Water Atlantis dC18 columns (3 um, 2.1 X 100 mm), gradient 5-100% B (A: water/ 0.1% formic acid, B= acetonitrile/ 0.1% formic acid) over 7 min, injection volume 3 ul, flow = 0.6 ml/min. UV spectra were recorded at 215 nm using a Waters 2996 photo diode array or on the Shimadzu 2010 system. Mass spectra were obtained over the range m/z 150 to 850 at a ng rate of 2 scans per second using Waters ZQ and over m/z 100 to 1000 at a sampling rate of 2Hz using Electrospray ionisation, by a Shimadzu 2010 LC-MS system. Data were integrated and reported using OpenLynx and OpenLynX Browser software or via Shimadzu PsiPort software.
Example 1 Reaction Scheme 1 9H 11 E N N / CIMCI| X / / \ CI \ 0\ R2 —>R2 / / 0 X X Stage 1 Stage 2 N \ N HKL NJ§N R4 I R3 ' / OH I \ / \ N\R3 R2 R2 / O / 0 Stage 3 X Stage 4 X Referring to Reaction Scheme 1, Stage 1, to a d suspension of dichloropyrirnidine (leq) in l,4-dioxane (lSvol) was added boronic acid (0.7eq) and Pd(PPh3)4 eq). A 2M K2CO3 solution (7.5vol) was added to the resulting mixture, which was heated at 900C overnight under an atmosphere of N2. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc : water (1 : l) (lOOvol) and the resulting solution filtered through celite. The organic layer was separated and the aqueous layer further ted with EtOAc (5 Ovol).
The combined organic layers were washed with saturated aqueous NaCl (20vol), dried over Na2SO4, filtered and the solvent removed in vacuo. The ing residue was purified by flash column chromatography (eluent: [0:1 to 1:19] EtOAc:heptane) to afford the required target compounds.
Referring to Reaction Scheme 1, Stage 2, 4-chlorosubstituted-phenyl- pyrimidine (leq), PdCl2(dppf).DCM (0.05eq) and triethylamine (2eq) were suspended in degassed MeOH (50vol) in a bomb fitted with a magnetic stirrer bar. The atmosphere in the reaction vessel was replaced with N2 by sive evacuation and ng with N2 gas (this process was repeated three times). The bomb was then flushed with CO by successive charging with CO and evacuation. The vessel was pressurised to 5bar of CO and heated at 500C with stirring for 5 hours. The reaction vessel was allowed to cool to room temperature before venting CO and flushing with N2. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc (3Ovol) and water (3 Ovol). The solution was filtered h cotton wool and the organic layer was separated, washed with ted aqueous NaCl (1 5vol), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography t: [0:1 to 1:9] EtOAc:heptane) yielded the target compounds.
Referring to on Scheme 1, Stage 3, 6-substituted-phenyl-pyrimidine- oxylic acid methyl ester (leq) was suspended in MeOH (20vol), lM NaOH solution (20vol) and stirred at room temperature for 4 hours. The reaction mixture was acidified with 2M HCl. Soluble products were extracted with DCM (2 x 20vol) and the combined organic layers were dried over MgSO4, filtered and concentration under reduced pressure afforded the target nds. Insoluble products were filtered, washed with water (3 x 10Vol) and heptane (3 x 10Vol) before drying in vacuo to yield the target compounds.
Referring to Reaction Scheme 1, Stage 4, the required amide analogues were prepared following the procedures described in method A, B, C or D.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result Weight 264.67 [M+H]+ = 7, 100% @ rt = 3.53 and 3.70 min 276.72 [M+H]+ = 277/279, 99.9% @ rt = 4.32 min 232.22 [M+H]+ = 232, 100% @ rt = 3.52 min 246.24 [M+H]+ = 247, 100% @ rt = 3.66 min \ OH N¢\N [M+H]+= 261.4, 100% @ | rt = 4.13 min \ OH [M+H]+= 252, 99% @ rt = WP] 2.32 min \ OH NAN [M+H]+= 320, 97% @ rt = H | 2.29 mm / o (1 OH Reaction Scheme 2 B(OH)2 NAlN N / IN 0 \ \ CI COOH Stage 1 CI Stage 2 N02 NH2 Referring to Reaction Scheme 2, Stage 1, to a degassed stirred solution of 4-chlor0nitro-benzene c acid (1eq) and 4,6-dichlor0pyrimidine (1 .44eq) in 1,4- dioxane (16vol) and 2N K2CO3 (8vol) was added Pd(PPh3)4 (0.06eq) and the e heated to 90°C for 3.75 hours under an atmosphere of nitrogen gas. The cooled reaction mixture had the solvents removed under reduced pressure. DCM (25vol) and water (25vol) were then added and the undissolved al removed by filtration through celite. The organic phase from the filtrate was concentrated under reduced pressure whilst adsorbing on to silica gel (8.2g). The residue was purified using dry flash chromatography (gradient up to 10% EtOAc:heptane) to afford the target compound.
Referring to Reaction Scheme 2, Stage 2, in a metal vessel equipped to carry out high pressure reactions, a degassed suspension of 4-chloro(4-chloronitro- phenyl)-pyrimidine (1eq) was stirred in MeOH (62vol). Triethylamine (2eq) and Pd(PPh3)4 (0.05eq) was then added and the vessel . The vessel was then charged with carbon monoxide gas to a re of 5 bar and heated to 50°C for 18 hours. After ion of excess carbon monoxide gas, the organic solvent was trated under reduced pressure. To the residue was added DCM (26vol) and the undissolved material was filtered off and washed with DCM (lOvol). The filtrate was washed with 2N HCl (lOvol), a 1:1 mixture of water and brine ) and then concentrated under reduce pressure whilst adsorbing onto silica gel (3.2g). The residue was purified by dry flash column chromatography (gradient up to 60% EtOAc:heptane) to give a mixture of products, the major identified as the methyl ester. The solid was then dissolved in 2N HCl (30vol) and washed with TBME (l x 30 vol & l x 20 vol). The aqueous layer was adjusted to pH7 and the precipitate formed was filtered off, washed with water (2 x 5vol) and air dried to afford the target compound.
Structure Molecular Weight Mass Spec Result [M+H]+ = 250/252, N/ N 96%@rt=3.43 \ 0 min Example 3 Reaction Scheme 3 B(OH) WI“ NAN 2 CIMCI NAN \ | _. CI 0\ CI CI CI | Stage 1 ? Stage 2 Stage 3 Cl 0\ 0\ N N lN {—1 N¢\|N | o \ \ O\ \ OH O\ —> —’ —> 0 0 Cl 0 CI Stage 4 CI O Stage 5 OH Stage 6 OH p N¢\N N¢\N \ OH l \ H Stage 7 0 CI Stage 8 o/ on O o E? Referring to Reaction Scheme 3, Stage 1, 5-bromochloro anisole (leq) in toluene (8vol) and THF (3vol) at -780C was added n-BuLi (1 .5eq) drop wise. The resulting mixture was d at -780C for 30 minutes under an atmosphere ofN2.
Trimethylborate (2eq) was then added to the reaction mixture and this was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with 1M HCl and the organic layer was separated. The organic layer was washed with saturated aqueous NaCl (20vol), dried over Na2SO4, filtered and the solvent removed in vacuum. The ing residue was d by flash column chromatography (eluent: [1 :1] EtOAc:heptane) to afford the required target nd (1 . 15g, 31%).
Referring to Reaction Scheme 3, Stage 2, to a stirred suspension of dichloropyrimidine (leq) in 1,4-dioxane (20vol) was added c acid (0.7eq) and Pd(PPh3)4 (0.05eq). A 2M K2CO3 on (lOvol) was added to the resulting mixture, which was heated at 900C for 3 hours under an atmosphere ofN2. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc : water (1:1) (lOOvol) and the resulting solution filtered through celite. The organic layer was ted and the aqueous layer further extracted with EtOAc (5 Ovol).
The combined organic layers were washed with saturated aqueous NaCl (20vol), dried over Na2SO4, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (eluent: [1:8] EtOAc:heptane) to afford the required target compound (1 . 14g, 73%).
Referring to Reaction Scheme 3, Stage 3, rosubstituted-phenylpyrimidine (leq), PdCl2(dppf).DCM q) and triethylamine (2eq) were suspended in degassed MeOH (50vol) in a bomb fitted with a ic stirrer bar. The atmosphere in the reaction vessel was replaced with N2 by successive evacuation and charging with N2 gas (this process was repeated three times). The bomb was then flushed with CO by successive charging with CO and evacuation. The vessel was pressurised to 5bar of CO and heated at 500C with stirring for 16 hours. The reaction vessel was allowed to cool to room temperature before venting CO and flushing with N2. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc ) and water (3 Ovol). The organic layer was separated, washed with saturated aqueous NaCl (15vol), dried over , filtered and concentrated under reduced pressure. Purification by flash column chromatography (eluent: [2:3] EtOAc:heptane) yielded the target nd (1.15g, 96%).
Referring to Reaction Scheme 3, Stage 4, to a solution of 6-Substitutedphenyl-pyrimidinecarboxylic acid methyl ester (leq) in DCM (80vol) at -780C was added BBr3 (3eq) under en. The on mixture was warm to 00C and stirred for lhour then allowed to stir at room temperature for 16 hours. The reaction mixture was poured into ice (lOOvol) and ted with EtOAc (lSOvol). The organic layer was separated, washed with saturated aqueous NaCl (1 5vol), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture (0.45 g) was used in the next step without further purification.
] Referring to Reaction Scheme 3, Stage 5, a solution of tituted- phenyl-pyrimidinecarboxylic acid (leq) in MeOH (lOOvol) was added concentrated H2SO4 (2 drops). The reaction mixture was refluxed for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc (3Ovol) and water (3 Ovol). The organic layer was separated, washed with ted aqueous NaCl ), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture (0.48g) was used in the next step without fiarther purification.
Referring to Reaction Scheme 3, Stage 6, to a solution of titutedphenyl-pyrimidinecarboxylic acid methyl ester (1 .05eq) in THF (lOvol) were added 3- hydroxy furan (leq) and PPh3 (l .5eq) under nitrogen. The reaction mixture was cooled to 00C and DIAD (l .5eq) was added slowly. Reaction e was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo and the resulting residue was ated with EtOAc and heptane (l :2) and solid was filtered to give the desired compound (0.42g, 70%).
Referring to Reaction Scheme 3, Stage 7, 6-substituted-phenyl-pyrimidine- 4-carboxylic acid methyl ester (leq) was suspended in THF (20vol), 2M NaOH (3.l4ml, 6.28mmol, Seq) and stirred at room temperature for 4 hours. The THF was removed under vacuo, MeCN (lOvol) was added and the reaction mixture was acidified with 6M HCl.
The resulting solid was filtered and washed with water and a mixture of MeCN: water (1 :l) to give desired product (0.335g. 83%).
Referring to Reaction Scheme 3, Stage 3, the required amide analogue was ed following the procedure described in method B.
The following compounds were ed substantially as described above.
Structure Molecular Mass Spec Result Wei_ht NM [M+H]+ = 321/323, 100% \ o @rt=3.55-3.82 min NAN [M+H]+ = 397/399, 98% @ \ N rt = 3.7 min 0 / CI N Example 4 Reaction Scheme 4 (\N (\N OH O o 0 Cd —> 0Q —> I 0 Stage 1 Stage 2 N Stage 3 I 0d ‘/\N N |N N¢\N \ NAIN CI \ O\ I \ OH —> fl CI 0—. 0 N¢\N | H O Q| / Stage 7 Referring to Reaction Scheme 4, Stage 1, N-(2-hydr0xyethy1)morpholine (leq) in DCM (70V01) at 00C was added dibromo nyl phosphorane (1.2eq). The reaction mixture was allowed to warm to room ature and stirred for 16 hrs. The solvent removed in vacuum. DCM (lOvol) was added to the reaction mixture. The precipitate was filtered to afford the target compound. The crude mixture was used in the next step without further purification.
Referring to Reaction Scheme 4, Stage 2, N-(2-bromoethyl)morpholine (1.1eq) in DMF (lSvol) were added 2-chloroiodophenol (leq) and Cs2CO3 (2.5eq).
The reaction mixture was refluxed for 3hours under nitrogen. The reaction e was allowed to cool to room temperature and EtOAc (40vol) and aq ammonia ) were added. The organic layer was separated and the aqueous layer further extracted with EtOAc (5Ovol). The combined organic layers were washed with saturated aqueous NaCl (20vol), dried over Na2CO3, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (eluent: [3:1] EtOAc:heptane) to afford the required target nd.
Referring to Reaction Scheme 4, Stage 3, to a stirred suspension of 3- subtituted-4 —chloro-iodobenzene (leq) in degassed DMF (lSvol) was added bis-diborane (l .05eq), Pd(OAc)2 (0.04eq) and KOAc (3.0eq). The reaction e was heated at 900C for 5hrs under an atmosphere ofN2. The reaction mixture was cooled to room temperature and filtered through celite then concentrated in vacuo to give crude product.
Crude was used in the next step without further ation.
] Referring to Reaction Scheme 4, Stage 4, to a stirred suspension of dichloropyrimidine (leq) in l,4-dioxane (90vol) was added boronic ester (1 .Oeq) and Pd(PPh3)4 (0.03eq). A 2M K2CO3 (3eq) solution was added to the ing mixture, which was heated at 900C for 16hrs under an atmosphere ofN2. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc : water (1 : l) (lOOvol) and the resulting solution filtered through celite. The organic layer was separated and the aqueous layer further extracted with EtOAc (5 Ovol).
The ed c layers were washed with saturated aqueous NaCl (20vol), dried over Na2SO4, d and the solvent removed in vacuo. The resulting residue was purified by flash column tography (eluent: [3:1] heptane) to afford the ed target compound.
Referring to Reaction Scheme 4, Stage 5, 4-chlorosubstituted-phenylpyrimidine (leq), PdCl2(dppf).DCM (0.05eq) and triethylamine (2eq) were suspended in degassed MeOH (50vol) in a bomb fitted with a magnetic stirrer bar. The atmosphere in the on vessel was replaced with N2 by successive evacuation and charging with N2 gas (this process was repeated three times). The bomb was then flushed with CO by successive charging with CO and evacuation. The vessel was pressurised to 5bar of CO and heated at 500C with stirring for 16 hours. The reaction vessel was allowed to cool to room temperature before venting CO and flushing with N2. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc (3Ovol) and water (3 Ovol). The organic layer was separated, washed with saturated aqueous NaCl (lSvol), dried over Na2SO4, filtered and concentrated under d pressure. Purification by re- crystallisation using MeOH d the target compound. ing to Reaction Scheme 4, Stage 6, 6-substituted-phenyl-pyrimidine- 4-carboxylic acid methyl ester (leq) was suspended in THF (20vol), 2M NaOH (2.5eq) and stirred at room temperature for 4 hours. Solvent (THF) was d and reaction mixture was acidified with 2M HCl. Resulting solid was filtered and was with water to give desired product.Referring to Reaction Scheme 4, Stage 7, the required amide analogue was ed following the procedure described in method B.
The ing compounds were prepared ntially as described above.
Structure Molecular Weight Mass Spec Result NAN 400.26 [M+H]+ = 364, \' o 98%@rt=2.4l 0 min O\/\N7. CI N¢\N 439.91 [M+H]+ = 440, \' N \ N 99%@rt=2.54 0 \Q min O\/\NOo NAN 292.72 [M+H]+ = 293/295, WWI 100% @.rt=4.18 A min 306.75 [M+H]+ = 307/309, W0IN 100%@rt=4.10 /I\ O 318.76 N/ [M+H]+ = 319, IN 100% @ rt = 4.61 \ OH O min NAN 306.75 = 307/309, I 100% @ rt = 4.37 \ O V10 0 N¢\N 306.75 [M+H]+= 307/309, I 100% @ rt = 4.37 \ OH \A o 290.71 [M+H]+= 291/293, N¢\N I 100% @ rt = 3.93 \ OH H1111 346.69 [M+H]+= 347/349, N¢\N F I 92/8% @ rt = 4.22 liF \ OH W 304.79 [M+H]+= 305/307, 100% @ rt = 4.20 / OH & o 360.82 [M+H]+= 362/364, W 100% @ rt = 2.55 / min 303.75 [M+H]+: 304, N N I 100% @ rt = 3.78 \ OH 111111 307.67 [M+H]+: 286/288, N¢\|N 99% @ rt = 3.26 \ OH / 111111 \ O 363.8 [M+H]+ = 364/366 NAIN 100% @ rt = 2.29 o/fi \ OH 111111 K/N\/\0 o 302.72 —= 303/305 N¢\N 100% @ rt = 4.14 \ OH min V0 0 305.89 [M+H]+ = 307/309, I 95%@ rt = 3.37 \ OH ofl o NAN 289.71 [M+H]+: 290, I 100% @ rt = 3.74 \ OH 111111 Example 5 Reaction Scheme 5 N/SN N/SN C“3'R2 NAN o WMCI| R1)\/kNH2| o" "o WMH’S‘RZ| O¢ " Stage 1 Stage 2 CIJLRS NIAN O R1MNJLR3 Stage 3 ] Referring to Reaction Scheme 5, Stage 1, 4-(chlorosubstituted)-phenyl- pyrimidine (leq) was suspended in l,4-di0xane (3vol) and um hydroxide (6vol) was added to the suspension. The reaction mixture was heated at 950C in a pressure tube for 16 hours with stirring. The reaction mixture was cooled to room ature and the precipitate was filtered off and washed with water to yield the target compound.
Referring to Reaction Scheme 5, Stage 2, 6-(substituted-phenyl)— pyrimidinylamine (leq) was suspended in oxane (20vol). Sodium hydride (6eq) was added and the suspension was stirred for 1 hour at ambient temperature. 3- Pyridinesulfonyl chloride or benzenesulfonyl chloride (1 .2eq) were added and the reaction mixture was stirred at 800C for 24 hours. In the case of pyridinesulfonyl chloride derivative, the reaction was quenched by the addition of water and the solvent was removed in vacuo. Purification by flash column chromatography (eluent: [0:1 to 1:4] MeOH:EtOAc) afforded the target compound. In the case of benzenesulfonyl chloride derivative, acetonitrile/water was added and the solid filtered off The filtrate was concentrated in vacuo and the residue was triturated in EtOAc to filrnish the sodium salt as a powder. The sodium salt was then washed with a citric acid aqueous solution followed by water and dried to filI'IllSh the desired compound.
Referring to Reaction Scheme 5, Stage 3, 6-substituted-phenyl-pyrimidin- 4-ylamine (leq) was ded in 1,4-dioxane or DMF (20vol). Sodium hydride (3eq) was added and the suspension stirred for 10 to 60 minutes at room temperature. The appropriate acid chloride (1 .Seq) was added and the on mixture stirred at room temperature for 1 hour. The reaction was monitored by LCMS. If the reaction was not complete, sodium e (leq) was added to the reaction mixture, which was then heated at 500C for 16 hours. Upon completion, the reaction was ed with water. If precipitation occurred, the itate was filtered and purified further by flash column chromatography using an riate eluent, if not the desired material was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried with MgSO4, filtered and the solvent removed in vacuo. The desired compound was fiarther purified either by trituration or prep HPLC when required.
The ing compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result Wei ; ht [M+H]+=402, 99% @ rt = NAIN 4.53 min \ N’8 A H I) =420, 100% @ rt = N¢\N 4.61 min \ \\S// A H [M+H]+=486, 100% @ rt = NAN 5.01 min | \\ // \ /s A H [M+H]+=487, 100% @ rt = N¢\N 4.91 min [M+H]+=420, 99.5% @ rt = NAIN 4.51 min [M+H]+=366, 100% @ rt = 4.28 min Example 6 Reaction Scheme 6 R1 —>R1 Stage 1 Referring to Reaction Scheme 6, Stage 1, to a stirred on of 6-(3- chloro-phenyl)-pyrimidinecarboxylic acid (leq) or -dichloro-phenyl)- pyrimidinecarboxylic acid methyl ester in THF ) was added dropwise a 1M NaOH solution. The mixture was stirred at ambient temperature and the resulting precipitate was filtered and washed with water/THF or with water then heptane to furnish the described salts.
Structure Molecular Mass Spec Result Wei ; ht [M+H]+= 291/293, 100% N¢\|N @ rt = 3.97 min A O [M+H]+= 362/364, 100% Ni“ @ rt = 2.55 min O / N\/\O [M+H]+= 307/309, 100% NAIN @ rt = 4.35 min ¢\ [M+H]+= 286/288, 99% @ N\ l” rt = 3.26 min l Na+ \N 0 NAN [M-Na+2H]+ = 364/366 of + 100% @ rt = 2.29 min o/fi \ Na K/N\/\O 0 [M+H]+ = 307/309, 87%@ N4\N rt = 3.37 min \ o’ Na+ Reaction Scheme 7 \N HCI \N l l H / OH / N‘R2 0 R1 —> R1 . O O O 0\ R1080 Stage 2 or / / Stage 4 B r Stag“ \N | , \NHCI + / O K I / OH R1 —> 0 R1 Stage 3 0 Referring to Reaction Scheme 7, Stage 1, to a stirred suspension of 4- bromo-pyridinecarboxylic acid methyl ester (1eq) in 1,4-dioxane (20vol) was added the appropriate substituted phenyl boronic acid (1 . 1eq) and Pd(PPh3)4 q). A 2M K2CO3 solution (7.5vol) was added and the reaction mixture was heated at 900C with stirring for 16 hours under an atmosphere of N2. The reaction mixture was cooled to room temperature and the resulting precipitate was isolated by filtration to furnish the acid intermediate as the potassium salt, which was used without further ation in the stage. In the case of the r0phenyl analogue no precipitate was formed upon cooling, hence the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc and water. Both phases were separated. EtOAc was removed in vacuo and the resulting residue was purified by flash column chromatography (eluent: [5:95] methanol:DCM) to furnish the desired hloro-phenyl)-pyridinecarboxylic acid methyl ester. The aqueous phase was acidified and the ing precipitate was isolated by ion and used as such in stage 2. Further purification was carried out by prep HPLC to furnish the required 4-(3-chloro-phenyl)-pyridinecarboxylic acid.
Referring to on Scheme 7, Stage 2, the required amide analogues were prepared following the procedure described in method A from 4-(3-chloro-phenyl)- pyridinecarboxylic acid, hydrochloride salt and were purified by trituration in acetonitrile/water (l/ l) or in water followed by heptane.
Referring to Reaction Scheme 7, Stage 3, the potassium salt isolated in stage 1 was suspended in HCl (2M) and stirred at ambient ature for 2 hours. The solid was filtered and washed with water to furnish the desired target compound.
Referring to Reaction Scheme 7, Stage 4, the required amide analogues were prepared following the procedure described in method A from 4-(substituted- phenyl)-pyridinecarboxylic acid potassium salt and were purified by trituration in acetonitrile/water (l/ l) or in water followed by heptane.
The following compounds were prepared substantially as bed above. ure Molecular Wei_ht Mass S n ec Result 289.72 / N [M+H]+= 290/292, 98% @ | rt = 3.31 min \ o A O / 305.76 N [M+H]+=306/308, 99% @ ' rt = 3.73 min \ o \/§\O 0 [M+H]+ 306/308, 99% @ / IN rt = 3.71 min [M+H]+=292/294, 100% @ rt = 3.44 min Example 8 Reaction Scheme 8 + F O F F N\\\N F\‘B*'F 5L3; F/Fo FJVO | F —> —>F F Stage 1 F Stage 2 F740$ CI CI CI ii\ ““1“ ”I“ Cl Cl \ \ F CI \ ' O F/i\ /i\ o F 0 Stage 3 F Stage 4 F CI CI N%\N I W‘IN \ O\ \ OH J} 0 J} O F 0 Stage 5a F N%\|N N IN + \ 0’ \ o\ Na k O 0 St 5b F/Fo age F 0 F F CI Referring to Reaction Scheme 8, Stage 1 a solution ofNaN02 (2.4eq) in water (5vol) was slowly added over 30 min to a suspension of [3-chloro (trifluoromethoxy)phenyl]amine (leq) in (7vol) of 15% HCl at -50C. The solid material was removed by ion and a solution ofNaBF4 (l .6eq) in water (4vol) was mixed with the filtrate. The resulting solid was collected by filtration, washed with minimum water and dried on a sinter funnel under vacuum for 1 hour. It was then dried in the vacuum oven at 400C until constant weight to give the required product. ] ing to Reaction Scheme 8, Stage 2, 3-chloro (trifluoromethoxy)benzene-l-diaz0nium tetrafiuoroboranide (1 eq) was mixed with bis(pinacolato) diboron (1.05eq) in a flask cooled by an ice bath. MeOH (8vol) was added and the mixture was de-gassed with nitrogen for 10 minutes before PdCl2(dppf)2.DCM (0.025 eq) was added. The mixture was stirred at room temperature overnight before is by LCMS. The reaction was evaporated to dryness, re-dissolved in DCM, dry loaded onto silica and d by dry flash chromatography g a slow gradient from 0-20% EtOAc in heptane. Clean fractions were combined and evaporated to dryness to give the ed product as an oil.
Referring to on Scheme 8, Stage 3, 4,6-dichloropyrimidine (leq) and 2- [3 -chloro(trifluoromethoxy)phenyl] -4,4,5 ,5 -tetramethyl- l ,3 ,2-dioxaborolane (0 . 7eq) were dissolved in dioxane (l2vol) at room temperature and 2M ium carbonate (2eq) was added. The solution was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (0.05eq) was added and the reaction was stirred at 900C for 2 hours before analysis by LCMS. The reaction was cooled to room temperature and the solvent was evaporated. DCM was added and the organic layer was washed with water, brine and dried using MgSO4. The solvent was evaporated to dryness to give an oil which was purified by dry-flash chromatography eluting with 0-6% EtOAc in heptane. The resulting oil was dried in the vacuum oven at 400C to give the required product.
Referring to Reaction Scheme 8, Stage 4, 4-Chloro(3-chloro trifluoromethoxy-phenyl)-pyrimidine (1 eq), and triethylamine (2eq) were dissolved in MeOH and degassed for 5 minutes with nitrogen. Pd(dppf)2Cl2.DCM (0.05eq) was added and the on was sealed inside a 500ml bomb. The bomb was charged with CO (5 bar) and heated at 500C overnight before analysis by LCMS. The reaction was cooled to room temperature and the solvent evaporated. The residue was solved in EtOAc and washed with water, brine and dried using MgSO4. The solvent was evaporated and the resulting solid purified by dry flash chromatography eluting with 30-40% EtOAc in e to give the required product. ] ing to Reaction Scheme 8, Stage 5a, 6-(3-Chloro trifluoromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester was dissolved in THF (l6vol) and 2M NaOH (2eq) was added. The reaction mixture was allowed to stir at room ature for 17 hours. Water (32vol) was added and the mixture extracted with EtOAc (2 x 32vol). 2 M HCl (2eq) was added and the solution extracted with EtOAc (3 x 32vol). The combined organic layers were dried over MgSO4 and the solvent removed to dryness. The crude compound was re-crystallised from acetonitrile (20vol), filtered and dried in a vacuum oven at 400C to give the desired target 6-(3-chlorotrifluoromethoxy- phenyl)-pyrimidinecarboxylic acid.
Referring to Reaction Scheme 8, Stage 5b, 6-(3-Chloro trifluoromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester was dissolved in THF. 2M NaOH (2eq) was added and the reaction was stirred at room temperature for 12 hours before is by LCMS. The reaction was evaporated to dryness and the resulting solid was washed with water and diethyl ether. The solid was dried in a vacuum oven at 400C to give the target compound 6-(3-chlorotrifluoromethoxy-phenyl)-pyrimidine carboxylic acid as a sodium salt.
The ing compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result Wei ; ht [M+H]+ = 319/321, 74% \I @ rt = 4.32 min Pi 0 F O NAIN [M+H]+= 319/321, 100% @ rt = 4.19 min \ O Na+ XF 0 F 0 Example9 Reaction Scheme 9 F F N\\\N F/[o FJVO F Stage 1 F Stage 2 m / N \ | Br COZMe \ F COH F 0 Stage 3 F ing to Reaction Scheme 9, Stage 1 a solution ofNaN02 (2.4eq) in water (5vol) was slowly added over 30 min to a sion of [3-chloro (trifluoromethoxy)phenyl]amine (leq) in (7vol) of 15% HCl at -50C. The solid material was removed by filtration and a solution ofNaBF4 (l .6eq) in water (4vol) was mixed with the filtrate. The resulting solid was collected by filtration, washed with m water and dried on a sinter funnel under vacuum for 1 hour. It was then dried in the vacuum oven at 400C until constant weight to give the required product.
] Referring to Reaction Scheme 9, Stage 2, 3-chloro oromethoxy)benzene-l-diazonium tetrafiuoroboranide (1 eq) was mixed with bis(pinacolato) diboron (1.05eq) in a flask cooled by an ice bath. MeOH (8vol) was added and the mixture was de-gassed with en for 10 minutes before PdCl2(dppf)2.DCM (0.025 eq) was added. The mixture was stirred at room temperature overnight before analysis by LCMS. The reaction was evaporated to dryness, re-dissolved in DCM, dry loaded onto silica and purified by dry flash chromatography running a slow nt from 0-20% EtOAc in heptane. Clean fractions were combined and evaporated to dryness to give the required product as an oil.
Referring to Reaction Scheme 9, Stage 3, to a stirred suspension of 4- bromo-pyridinecarboxylic acid methyl ester (leq) in oxane (20vol) was added the appropriate substituted phenyl boronic acid (1 . leq) and Pd(PPh3)4 (0.05eq). A 2M K2CO3 solution (7.5vol) was added and the reaction mixture was heated at 900C with stirring for 16 hours under an here of N2. The reaction mixture was cooled to room temperature and the resulting precipitate was isolated by filtration to furnish the acid product as the potassium salt which was suspended in HCl (2M) and stirred at ambient temperature for 2 hours. The solid was filtered and washed with water to furnish the desired target compound.
The following compounds were prepared substantially as described above.
Structure lar Mass Spec Result Wei ; ht / N 317.65 [M+H]+=3l7, 100% @ rt I = 3.76 min \ OH Example 10 Reaction Scheme 10 Br Br \ Br Br HO \/\0 Stage 1 Stage 2 HO Stage 3 CI CI CI CI ‘Stage 4 Né\N (ID/Q Br \ O\ <— (D 0 Stage 6 (ID/B\O Stage 5 0 CI [ Stage7 N¢\N Referring to Reaction Scheme 10, Stage 1. Sodium hydride (1.1eq) was added portion wise to a cool (00C), stirred solution of 4-bromochlorophenol (1.0eq) in DMF (6vol) and the e stirred at this temperature under a nitrogen atmosphere for minutes. After this time, 3-bromoprop-l -ene (1.1eq) was added dropwise and the on mixture was allowed to warm to room temperature before being stirred at this temperature ght. After this time, the reaction mixture was poured onto ice-water (lOvol), the mixture was extracted with ethyl acetate (3 x), the organic layers were combined, washed with brine (5vol), dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 20% ethyl acetate, 80% e) to give the desired compound as a yellow gum.
Referring to Reaction Scheme 10, Stage 2. l-Allyloxybr0mochlor0 benzene (leq) was ded in lene (12vol) and the mixture heated to 1600C and stirred at this temperature overnight. After this time, the reaction mixture was cooled to room temperature and trated. The resulting residue was purified using a Biotage Isolera (340g silica column eluting with a gradient from e to 100% DCM) to give the desired compound as a yellow oil.
Referring to Reaction Scheme 10, Stage 3. Borane (1M solution in THF, leq) was added drop wise to a d solution of 2-allylbromochloro-phenol (leq) in THF (lOvol) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After this time, the reaction mixture was quenched by the sequential addition of water (leq), NaOH (leq) and hydrogen peroxide (leq) and the mixture stirred at room temperature for a fiarther 2 hours. The resulting mixture was ioned between diethyl ether (5vol) and water (5vol). The c layer was separated, washed with brine (2vol), dried (MgSO4), filtered and to give the desired compound as a colourless gum. ing to Reaction Scheme 10, Stage 3. Diethyl diazene-l,2- dicarboxylate (leq) was added dropwise to a stirred solution of triphenyl phospane (leq) and 4-bromochloro(3-hydroxy-propyl)-phenol (leq) and the on mixture was stirred at room temperature under a en atmosphere overnight After this time, the reaction mixture was concentrated and purified using a Biotage a (50g silica column eluting with a gradient from 0% heptane to 20% ethyl acetate / 80% heptane) to give the desired compound as a pale yellow oil.
Referring to Reaction Scheme 10, Stage 4. Bis-pinacol borane (l .5eq) was added in one portion to a cool (00C), stirred solution of 6-bromochloro-chroman (l .Oeq) and potassium acetate (3.5eq) in DMSO (5vol). The mixture was ed with nitrogen for 5 minutes, after which time f)2C12 (0.1eq) was added in one portion, the mixture was allowed to warm to room temperature and was stirred at this temperature under a nitrogen atmosphere for 1 hour. After this time the inorganic precipitate was removed by filtration and the filtrate was concentrated. The resulting residue was purified using a Biotage Isolera (50g silica column eluting with a nt from 0% heptane to 40% DCM / 60% heptane) to give the d nd as a pale yellow oil.
Referring to Reaction Scheme 10, Stage 5. Tripotassium phosphate (2eq) was added in one portion to a d solution of 8-chloro(4,4,5,S-tetramethyl- [l,3,2]dioxaborolanyl)-chroman (leq) and methyl 4-bromopyridinecarboxylate (2eq) in DMF (lOvol). The mixture was degassed with nitrogen for 5 minutes, after which time Pd(dppf)2C12 (0.2eq) was added in one portion, the mixture was then heated to 600C and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (5vol) and water (5vol). The c layer was separated, washed sequentially with water (5vol) then brine (5vol) before being dried (MgSO4), ed and concentrated. The resulting residue was purified using a Biotage Isolera (100g silica column eluting with a gradient from 0% heptane to 80% DCM / 20% heptane) to give the d compound as a white solid.
Referring to Reaction Scheme 10, Stage 5. 2M NaOH (4eq) was added in one portion to a stirred solution of 6-(8-chloro-chromanyl)—pyrimidinecarboxylic acid methyl ester (1 eq) in ethanol (lvol) and the mixture was stirred at room temperature for 2 hours. After this time the reaction e was d with water and the ethanol removed under reduced pressure. The remaining solution was acidifed to pH 1 with 1M HCl and the resulting precipitate was collected by filtration, washed with water (5vol) and TBME (Svol) and dried in a vacuum oven at 400C overnight to afford the desired compound as a white solid.
The following compounds were prepared ntially as described above.
Structure Molecular Mass Spec Result Wei_ht /\ [M+H]+= 291, 100% @ rt NI \ N = 3.71 min / o Example 11 Reaction Scheme 11 W Br HogBr Br —> O —> / —> O ii \ Stage 1 EA O Stage 2 0 Stage 3 / ' f l Stage4 NAP] N¢\|\J \ OH \ O\ / / Stage 5 0 Referring to Reaction Scheme 11, Stage 1. ium carbonate (2eq) was added portion wise to a stirred solution of 4-bromochlorophenol (leq) and bromoacetaldehyde diethyl acetal (1 .Seq) in DMF (6V01) and the mixture was heated to 1400C and heated at this temperature under a nitrogen atmosphere for 3 hours. After this time the reaction mixture was cooled to room temperature and concentrated. The resulting residue was partitioned n ethyl acetate (20V01) and water (5V01), the organic layer was separated, dried ), filtered and concentrated. The resulting e was d using a Biotage Isolera (340g silica column eluting with a nt from 0% DCM to 60% DCM / 40% heptane) to afford the desired compound as a less oil.
Referring to Reaction Scheme 11, Stage 2. 4-Bromochloro(2,2- diethoxy-ethoxy)-benzene (leq) was added portion wise as a solution in toluene (5V01) to polyphosphonic acid (8eq)) at 00C. The ing suspension was d to warm to room temperature before being heated to reflux and stirred for 1 hour. After this time the e was cooled to room temperature and partitioned between water (10V01) and ethyl acetate (3 0V01). The resulting residue was partitioned between ethyl acetate (3 0V01) and water (5V01), the organic layer was separated, dried (MgSO4), filtered and concentrated.
The resulting residue was purified using a Biotage Isolera (340g silica column eluting with 100% heptane) to afford the desired compound as a white solid.
] Referring to Reaction Scheme 11, Stage 3. Potassium acetate (3eq) was added in one portion to a stirred solution of 5-bromochloro-benzofuran (leq) and bis- pinacol borane (1 .1eq) in DMF (3V01). The mixture was degassed with en for 5 minutes, after which time Pd(dppf)2C12 (0.3eq) was added in one portion, the mixture was then heated to 800C and stirred at this temperature for 18 hours under a en atmosphere. After this time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (20V01) and water (10V01). The biphasic suspension was filtered through glass fiber filter paper and the organic layer was separated, washed sequentially with water (3 x) before being dried (MgSO4), filtered and concentrated. The resulting e was purified purified using a Biotage Isolera (100g silica column eluting with 100% heptane to 50% DCM / 50% heptane) to afford the desired compound as a white solid.
Referring to Reaction Scheme 11, Stage 4. Tripotassium phosphate (1 .4eq) was added in one portion to a stirred solution of, 7-chloro(4,4,5,5-tetramethyl- [1,3,2]dioxaborolanyl)-benzofuran (1 eq) and methyl 6-chloropyrimidinecarboxylate (2eq) in DMF (4V01). The mixture was degassed with nitrogen for 5 minutes, after which time f)2C12 (0.2eq) was added in one portion, the mixture was then heated to 600C and stirred at this ature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (20vol) and water (10vol). The organic layer was separated, washed sequentially with water (10vol) then brine (10vol) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified purified using a Biotage Isolera (50g silica column g with 100% heptane to 20% ethyl acetate / 50% heptane) to afford the desired compound as a white solid.
Referring to Reaction Scheme 11, Stage 5. NaOH (1 .Seq) was added in one portion to a stirred solution of 6-(7-chloro-benzofiaranyl)-pyrimidinecarboxylic acid methyl ester (1 .0eq) in THF (8vol) and the mixture was stirred at room temperature for 16 hours. After this time, the resulting precipitate was collected by filtration, washed with water (1vol) and DCM (2vol) before being dried under vacuum. This solid was then suspended in HCl (2M solution, 6vol) and acetonitrile (6vol), heated to 800C until te dissolution then cooled to room temperature. The acetonitrile was removed under reduced re and the solid precipitate was collected by filtration, washed with water (lvol) before being dried in a vacuum over overnight to give the hydrochloride salt of the desired compound as a white solid.
The ing compounds were prepared ntially as bed above.
Structure Molecular Mass Spec Result Wei_ht NAN [M+H]+=275/277, 98% I @ rt = 3.70 min / OH Example 12 Reaction Scheme 12 NAN Stage 1 NAN Stage 2 CI/R/KCI| R1/R/KCI| R3 R3 NAN Stage 3 NAN RAW \| | O RAWOH R3 0 R3 0 Referring to Reaction Scheme 12, Stage 1. Potassium ate (2M solution, 52.0ml, 104.0mmol) was added in one portion to a d solution of 3,4- dichlorophenyl boronic acid (6.9g, 37.0mmol) and 4,6-dichloromethyl pyrimidine (8.5g, 52.0mmol) in dioxane (l50ml). The e was ed with nitrogen for 5 s, after which time ium tetrakis triphenylphosphine (3.0g, 3.0mmol) was added in one portion, the mixture was then heated to 900C and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in DCM (500ml), washed sequentially with water (500ml) then brine (500ml) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography on: 6% EtOAc, 94% Heptane) to give the desired compound (6.05g, 42% yield) as a white solid. SH (500 MHz, DMSO) 8.91 - 9.00 (l H, m) 7.88 - 7.96 (l H, m) 7.76 - 7.88 (l H, m) 7.58 = 2.30 min m/z - 7.69 (l H, m) 2.36 (3 H, s). Tr (ES+) (M+H+) 275, 277.
Referring to Reaction Scheme 12, Stage 2. Triethylamine (6.lml, 44.0mmol) was added in one portion to a meter containing a stirred solution of 4- chlor0(3,4-dichlor0-phenyl)methyl-pyrimidine (5.95 g, 22.0mmol) in methanol (80ml). The mixture was degassed with nitrogen for 5 minutes, after which time Pd(dppf)2Cl2 (0.9g, l.0mmol) was added in one portion, the calorimeter was sealed, pressurised with carbon monoxide (5 bar) and was heated to 500C overnight. After this time the on mixture was cooled to room temperature, diluted with methanol and concentrated. The resulting residue was dissolved in DCM ) and washed sequentially with water (250ml) and brine (25 0ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue d by flash column chromatography (elution: 40% EtOAc, 60% heptane) to give the desired compound (5.2g, 80% yield) as a white solid. SH (500 MHz, DMSO) 9.19 (1 H, s) 7.92 - 7.97 (1 H, m) 7.79 = 2.10 min - 7.85 (1 H, m) 7.63 - 7.70 (1 H, m) 3.95 (3 H, s) 2.30 - 2.42 (3 H, m). Tr m/z (ES+) (M+H+) 297, 299.
Referring to on Scheme 12, Stage 3. NaOH (2M solution, 1.1ml, 2.0mmol) was added in one n to a stirred solution of 6-(3,4-dichloro-phenyl) methyl-pyrimidinecarboxylic acid methyl ester (0.32g, 1.0mmol) in THF (10ml) and the mixture was stirred at room temperature for 16 hours. After this time, the resulting precipitate was collected by filtration, washed with water (1ml) and DCM (20ml) before being dried under vacuum. This solid was then suspended in HCl (2M solution, 60ml) and acetonitrile (60ml), heated to 800C until complete dissolution then cooled to room temperature. The itrile was removed under reduced pressure and the solid precipitate was collected by filtration, washed with water (10ml) before being dried in a vacuum over overnight to give the hydrochloride salt of the desired compound (0.22g, 75% yield) as a white solid.
The following compounds were prepared substantially as bed above.
Structure Molecular Mass Spec Result Wei_ht 304.72 [M+H]+= 7, 100% NAN @rt=3.64 min \ OH A 0 Example 13 Reaction Scheme 13 NIAN /\ Stage 1 NIAN Stage 2 NI \ N / O\ / OH R1 R1 0 R1/KfSéO O 0 Br OH Stage 3 NAN Stage 4 I NIAN / 0\ / R R1 O 0 o 0 | | Referring to on Scheme 13, Stage 1. Sodium bicarbonate (0.46g, .0mmol) was added in one portion to a stirred solution of 5-bromomethyl(3,4- dichloro-phenyl)-pyrimidinecarboxylic acid methyl ester (0.24g, 0.64mmol) in DMSO (5ml), and the mixture was stirred at room temperature under a nitrogen atmosphere for hours. After this time the mixture was partitioned between ethyl acetate (20ml) and water (20ml), the c layer was separated and the aqueous layer extracted with ethyl acetate (2 x 20ml). The c layers were combined, dried (MgSO4), filtered, concentrated and the resulting e was triturated with diethyl ether. The resulting precipitate was collected by filtration and dried under vacuum to give the desired compound (0.08 g, 45% yield) as an orange solid. ing to Reaction Scheme 13, Stage 2. Sodium methoxide (0.02g, 0.36mmol) was added in one portion to a stirred solution of 4-(3,4-dichloro-phenyl)—5H- furo[3,4-d]pyrimidinone (0.05 g, 0.18mmol) in methanol (5ml), and the mixture was stirred at room ature under a en atmosphere for 20 hours. After this time, sodium hydroxide (2M solution, 0.05ml, 0.89mmol) was added and the mixture was heated to 700C and stirred at this temperature for a further 4 hours. After this time the reaction mixture was cooled to room ature and the resulting precipitate was collected by filtration, washed with ol (5ml) and dried under vacuum to give the desired compound (0.01 g, 5% yield) as an off-white solid.
Referring to Reaction Scheme 13, Stage 3. Sodium methoxide (0.03 g, 0.53mmol) was added in one portion to a stirred solution of 5-bromomethyl(3,4- dichloro-phenyl)-pyrimidinecarboxylic acid methyl ester (0.1g, 0.26mmol) in methanol (5ml), and the mixture was stirred at room ature under a nitrogen atmosphere for hours. After this time the mixture was concentrated and the resulting residue taken up in DCM (10ml). The solution was washed consecutively with water (2 x 50ml) and brine (2 x 50ml), before being separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% DCM to 99% DCM: 1% Methanol) to give the desired compound (0.02g, 20% yield) as a white solid. Tr = 2.11 min m/z (ES+) (M+H+) 327, 329.
Referring to Reaction Scheme 13, Stage 4. Sodium hydroxide (0.05ml, l) was added in one n to a d solution of methyl 6-(3,4-dichlorophenyl)- -(methoxymethyl)pyrimidinecarboxylate (0.1 g, 0.26mmol) in THF (5ml) and the mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. After this time the resulting precipitate was collected by filtration, washed with water (1ml) and dried under vaccuum to give the desired compound (0.004g, 15% yield) as a white solid.
The following compounds were prepared substantially as described above. ure lar Mass Spec Result Wei_ht [M+H]+ = 303/305, 100%@ N IN rt = 4.20 min A 0 ¢\ [M+H]+ = 321/323, 100%@ N\ I“ rt = 3.29 min Ao OH N¢\N [M+H]+ = 317/319, 100%@ \ O rt = 3.89 min A o Example 14 Reaction Scheme 14 R 0 OH 0 OH Step 1 R Step 2 R CI CI ing to Reaction Scheme 14, Stage 1. 2,2-Dimethylpropanoyl chloride (0.07ml, 0.53mmol) was added dropwise to a stirred on of hloro cyclopropoxy-phenyl)-pyrimidinecarboxylic acid (0.15 g, 0.48mmol) in THF (10ml) and the mixture was stirred at room temperature for 2 hours. After this time the mixture was added portion wise to a solution of (lR)-l-[(3 aR,5R,6S,6aR)—6-hydroxy-2,2- dimethyl-tetrahydro-ZH-furo[2,3-d][l,3]dioxolyl]ethane-l,2-diol (0.32g, l.44mmol) in pyridine (10ml) and the on mixture was d at room temperature under a nitrogen atmosphere for 18 hours. The resulting mixture was concentrated and the residue partitioned n DCM (50ml) and water (20ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was then purified by flash column chromatography (elution: 100% ethyl acetate) to give the desired compound (0.095g, 34% yield) as a colourless oil. Tr = 1.95 min m/z (ES+) (M+H+) 493.
Referring to Reaction Scheme 14, Stage 2. 4M HCl in dioxane solution (5ml) was added in one portion to a stirred solution of 6-(3-chlorocyclopropoxy- phenyl)-pyrimidinecarboxylic acid 6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3- d][l,3]dioxolylmethyl ester (0.095 g, 0.19mmol) in dioxane (2ml) and the mixture was stirred at room ature overnight. The resulting mixture was concentrated and the resulting residue was then purified by prep HPLC to give the title compound (0.01 g, 13% yield) as a colourless glass.
Structure Molecular Wei_ht Mass S n ec Result 452.85 [M+Na]+ = 475.0 @ rt = 3.36+3.4lmin /\ \OH / o‘ N\ IN O Example 15 Reaction Scheme 15 OWO N¢\|N N¢\|N /_0 O \ \ < Step1 O\/ O\/ HO Step2 CI o o if; Step3 Qo O I N: IN \ OH 0 Step 4 O 0L0 \__0 Referring to Reaction Scheme 15, Stage 1. Triethylamine (19.01ml, 146.92mmol) was added dropwise to a solution of l butynedioate (25.0 g, 146.92 mmol) and formamidine hydrochloride (11.83 g, 146.92 mmol) in acetonitrile (500 mL).
The resulting red solution was heated at 800C for 2.5 hours. After this time the on mixture was cooled to 50C using a saturated ce bath and the reaction was stirred at this temperature for 25 minutes. After this time the resulting solid precipitate was collected under suction and dried on a sinter fimnel for 30 minutess under vacuum at room temperature before drying in the vacuum oven at room temperature for 3 hours to give the desired compound (21.3 g, 86% yield) as a pale brown solid. Tr = 0.85 min (3.5 minute ) m/z (ES+) (M+H+) 169.
Referring to Reaction Scheme 15, Stage 2. Ethyl 6-hydroxypyrimidine carboxylate (21.3 g, 126.67 mmol) was dissolved in dry DMF (100 mL) in a 2 neck flask.
The flask was purged with a stream of nitrogen while cooling in an ice bath for 10 minutes. After this time, thionyl chloride (15.6 mL, 215.6 mmol) was added dropwise over 20 minutes, before being warmed to room temperature and stirred under a nitrogen atmosphere for 2 hours. After this time, the on mixture was carefully poured onto ~100 mL ice water. TBME (100 mL) was added, the organic layer was separated and the aqueous ted with further TBME (3 x 100 mL). The combined organic layers were washed utively with water (2 x 100 mL), and brine (100 mL) before being dried (MgSO4), filtered and concentrated to give the desired compound (8.8 g, 37% yield) as a light orange powder. SH (500 MHZ, DMSO) 9.23 (d, J=0.95 Hz, 1 H), 8.16 (d, J=1.10 Hz, 1 H), 4.39 (q, J=7.09 Hz, 2 H), 1.34 (t, J=7.17 Hz, 3 H). Tr = 1.43 min (3.5 minute method) m/z (ES+) (M+H+) 187.
Referring to Reaction Scheme 15, Stage 3. Tripotassium phosphate (1.12 g, 5.63 mmol) was added in one portion to a stirred solution of 2-(2H-l,3-benzodioxol yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.93 g, 3.75 mmol) and ethyl 6- chloropyridinecarboxylate (0.7 g, 3.75 mmol) in DMF (20 mL). The mixture was degassed with nitrogen for 5 s, after which time Pd(dppf)2Cl2 (0.14 g, 0.19 mmol) was added in one portion, the mixture was then heated to 800C and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (200mL) and water ). The organic layer was separated, washed sequentially with water (100mL) then brine (100mL) before being dried (MgSO4), filtered and concentrated. The resulting brown solid was ed by flash column chromatography (elution: 40% EtOAc, 60% Heptane) to give the desired compound (0.31 g, 31% yield) as a white solid.
Tr = 1.87 min m/z (ES+) (M+H+) 273.
Referring to on Scheme 15, Stage 4. NaOH (2M solution, 0.63 mL, 1.27 mmol) was added in one n to a stirred solution of ethyl 6-(2H-l,3-benzodioxol- -yl)pyrimidinecarboxylate (0.31 g, 1.15 mmol) in THF (10mL) and the mixture was stirred at room temperature for 16 hours before being heated to reflux for 2 hours. After this time, the reaction mixture was cooled to room temperature and the ing precipitate was collected by filtration, washed with THF (20 mL) before being dried under vacuum to give the desired compound (0.17g, 56% yield, >99% purity) as a white solid.
The following compounds were prepared ntially as described above.
Structure Molecular Weight Mass Spec Result [M+H]+= 245/247, 99% @ rt = 3.08 min [M+H]+= 281/283, 99% @ rt = 2.61 min = 279/281,100% @ n = 3.65 min [M+H]+= 287/289, 100% @ rt = 3.03 min Example 16 Reaction Scheme 16 N¢\N NAIN Né\N I I \ o\/ —. \ O\/ _. \ 0 Step 1 Step 2 \s 0 0 0 R1 R1 CI CI CI R1 = MeS(O)— R1 = MeS(O)— R1 = MeS(O)2- R1 = MeS(O)2- ] Referring to Reaction Scheme 16, Stage 1. A solution of oxone (0.25 g, 0.40 mmol) in water (12 rnL) was added portion wise over 15 s to a stirred solution of ethyl 6-[3-chloro(methylsulfanyl)phenyl]pyrimidinecarboxylate (0.25 g, 81 mmol) in acetone (12 rnL) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time, the reaction was partitioned between water (20 rnL) and ethyl acetate (50 rnL). The organic layer was ted, and the aqueous further extracted with ethyl acetate (2 x 50 rnL). The combined organic extracts were then dried (MgSO4), filtered and concentrated. The ing residue was purified on a Biotage isolera (15% ethyl acetate, 90% heptanes to 100 % ethyl acetate) to give the desired compound (0.2 g, 76% yield) as a white solid. SH (500 MHz, 6) 9.48 (d, J = 1.20 Hz, 1H), 8.66 (d, J = 1.22 Hz, 1H), 8.56 (dd, J = 1.64, 8.22 Hz, 1H), 8.48 (d, J = 1.58 Hz, 1H), 8.02 (d, J = 8.21 Hz, 1H), 4.43 (q, J = 7.11 Hz, 2H), 2.87 (s, 3H), 1.38 (t, J = 7.11 Hz, 3H). Tr = 1.64 min m/z (ES+) (M+H+) 325, 327.
Referring to Reaction Scheme 16, Stage 2. NaOH (2M solution, 0.33 mL, 0.66 mmol) was added in one portion to a d solution of ethyl 6-(3-chloro methanesulfinylphenyl)pyrimidinecarboxylate (0.19 g, 0.61 mmol) in THF (30mL) and the mixture was stirred at room temperature for 7 hours. After this time, the resulting precipitate was collected by filtration, washed with THF (10 rnL) before being dried under vacuum to give the desired compound (0.17g, 84% yield, >99% purity) as a white solid.
The following compounds were ed substantially as described above.
Structure Molecular Weight Mass Spec Result \ O O [M+H]+=297/299 98.9% @ rt = 2.83min Cl \ O [M+H]+=313/315100%@rt=2.92 min Example 17 Reaction Scheme 17 0 CI Step 3 NAN NAN NAN I I I \ o \ o \ o\/ 0 Step 5 0 Step 4 O 0 CI 0 CI 0 CI Referring to on Scheme 17, Stage 1. Cyclopropylmagnesium bromide (0.5M solution in THF, 100.0mL, 50.0mm01) was added portion wise over 1 hour to a cold (-780C), stirred solution of 4-bromoch10robenza1dehyde (5.5g, .0mm01) in THF ) and the mixture was stirred for 1 hour before being allowed to warm to room temperature and d for a fiarther 18 hours. After this time, the reaction was quenched by the addition of saturated ammonium chloride (100mL) and the mixture extracted with ethyl acetate (3 x . The combined organic extracts were ed, washed with water (100mL) and brine (100mL) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 10% ethyl acetate, 90% heptanes) to give the desired compound (5.05g, 77% yield) as a pale yellow oil. SH (500 MHz, DMSO) 7.66 (d, J=1.89 Hz, 1 H) 7.50 - 7.60 (m, 2 H) 5.43 (br. s., 1 H) 4.59 (d, J=5.20 Hz, 1 H) 1.04 - 1.15 (m, 1 H) 0.29 - 0.46 (m, 4 H).
Referring to Reaction Scheme 17, Stage 2. Potassium acetate (3.72g, 40.0mm01) was added in one n to a stirred solution of (4-bromo chlorophenyl)(cyclopropyl)methanol (3.3g, 1.3mmol) and bis-pinacol borane (3.85 g, 1.5mmol) in DMSO (35mL). The mixture was degassed with nitrogen for 5 minutes, after which time Pd(dppf)2Cl2 (0.46g, 0.6mmol) was added in one portion, the mixture was then heated to 800C and stirred at this temperature for 16 hours under a en atmosphere. After this time the reaction mixture was cooled to room ature and partitioned between ethyl acetate (100mL) and water (50mL). The biphasic suspension was filtered through glass fiber filter paper and the organic layer was separated, washed sequentially with water (3 x 100mL) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 80% heptane, 20% DCM and 2mL of triethylamine) to give the d compound (3.5g, 90% yield) as a colourless oil. SH (500 MHz, DMSO) 7.61 (s, 2 H) 7.56 (s, 1 H) 5.39 (d, J=4.41 Hz, 1 H) 4.66 (t, J=5.20 Hz, 1 H) 1.24 - 1.36 (m, 12 H) 1.05 - 1.12 (m, 1 H) 0.24 - 0.47 (m, 4 H).
] Referring to Reaction Scheme 17, Stage 3. Tripotassium ate (1 .03g, 4.8mmol) was added in one portion to a stirred solution of [2-chloro(tetramethyl-1,3,2- dioxaborolanyl)phenyl](cyclopropyl)methanol (1.0g, 3.2mmol) and ethyl 6- chloropyrimidinecarboxylate (0.73 g, 3.89mmol) in DMF (20mL). The mixture was degassed with en for 5 minutes, after which time Pd(dppf)2Cl2 (0.13g, 0.16mmol) was added in one portion, the mixture was then heated to 600C and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100mL) and water (50mL). The organic layer was separated, washed sequentially with water (5 0mL) then brine (50mL) before being dried (MgSO4), filtered and trated. The resulting red gum was purified by flash column chromatography (elution: 40% EtOAc, 60% e) to give the desired compound , 65% yield) as a colourless oil. SH (500 MHz, DMSO) 9.42 (d, J=1.10 Hz, 1 H) 8.57 (d, J=1.10 Hz, 1 H) 8.22 - 8.36 (m, 2 H) 7.79 (d, J=8.20 Hz, 1 H) 5.52 (br. s., 1 H) 4.72 (d, J=5.99 Hz, 1 H) 4.43 (q, J=7.09 Hz, 2 H) 1.38 (t, J=7.09 Hz, 3 H) 1.15 - 1.22 (m, 1 H) 0.29 - 0.53 (m, 4 H). Tr = 2.27 min m/z (ES+) (M+H+) 321.
] Referring to Reaction Scheme 17, Stage 4. NaOH (2M solution, 0.24mL, 0.48mmol) was added in one portion to a stirred solution of ethyl 6- {3-chloro [cyclopropyl(hydroxy)methyl]phenyl}pyrimidinecarboxylate (0.16g, 0.48mmol) in THF (2mL) and the e was stirred at room temperature for 16 hours. After this time, the resulting precipitate was collected by filtration, washed with water (1mL) and DCM (20mL) before being dried under vacuum to give the desired compound (0.065 g, 41% yield) as a white solid.
Referring to Reaction Scheme 17, Stage 5. artin Periodinane (0.36g, 1.08mmol) was added portion wise to a cooled (00C), stirred solution of 6-{3- chloro[cyclopropyl(hydroxy)methyl]phenyl}pyrimidinecarboxylic acid (0.36g, 1.08mmol) in DCM (3mL) and the e was allowed to warm to room temperature and d for 18 hours. After this time, the e was partitioned between DCM (20mL) and saturated sodium bicarbonate (20mL). The organic layer was separated, washed with water (100mL) and brine (50mL) before being dried ), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 20% ethyl acetate, 80% heptanes) to give the desired compound , 74% yield) as a white solid.
The following compounds were prepared substantially as described above.
Structure lar Weight Mass Spec Result \ O O [M+H]+ = 305/307, 98%@ n = 3.25 min 0 CI \ 0 [M+H]+ = 303/305, 100%@ n = 3.54 min 0 CI Example 18 Reaction Scheme 18 (QBr 0 NéjN WW é \ OH \ OH _> \O _> —> | 0| Step 1 (Q Step 2 0 Step 3 /N O (3| I 0 0' H/Cl CI 0 CI Referring to Reaction Scheme 18, Stage 1. To a stirred solution of 4- bromochlorobenzaldehyde (0.51 g, 2.32 mmol) in a mixture of dry dioxane (2.5 mL) and dry DMF (0.60 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2- dioxaborolane (0.64 g, 2.52 mmol) and potassium acetate (0.7 g, 7.13 mmol). The mixture was degassed and then 1,1'-bis(diphenylphosphanyl)ferrocene - dichloropalladium (1 :1) (0.08 g, 0.11 mmol) was added. The mixture was further degassed before heating to 80°C for 3 hours under an atmosphere of nitrogen gas. To the cooled reaction mixture was added water (30 mL) and EtOAc (15 mL); the organic layer was then washed with a 3:1 e of water and brine (2 x 40 mL), brine (5 mL), dried (MgSO4), filtered and concentrated. The resulting residue was then absorbed onto silica gel (1.6 g) and purified by dry flash chromatography (0-20% EtOAc in heptane) to give the desired compound (0.25 g, 37% yield @ 90% NMR purity) as a white partial solid.
Tr = 1.46 min (63%) & 2.45 min (30%) m/z (ES+) (M+H+) no ionisation.
Referring to Reaction Scheme 18, Stage 2. To a degassed stirred solution of ethyl 6-chloropyrimidinecarboxylate (0.17 g, 0.9 mmol) and 2-chloro (tetramethyl-l,3,2-dioxaborolanyl)benzaldehyde (0.22 g, 0.81 mmol) in dioxane (2.5 mL) was added 2M K2CO3 (1.25 mL). Pd(PPh3)4 (57 mg, 0.05 mmol) was then added and the reaction mixture was r degassed before heating to 90°C under an atmosphere of nitrogen gas for 2 hours. After this time, the reaction mixture was cooled to room temperature and concentrated. Water (5 mL) was then added and the solid filtered, washed with water (2 mL), acetone (3 x 2 mL) and dried under vacuum. The solid was suspended in a mixture of EtOAc (30 mL) and 1N HCl (10 mL) and then heated to achieve partial solution. The cooled two-phase system was then sonicated to achieve full dissolution. The aqueous layer was re-extracted with EtOAc (10 mL); the combined organics were washed with brine (5 mL), dried (MgSO4), filtered and trated to give the d compound (0.1 g, 42% yield @ 85% ) as a beige solid. Tr = 1.58 min m/z (ES+) (M+H+) 263/265.
] Referring to Reaction Scheme 18, Stage 3. To a stirred suspension of 6-(3- chloroformylphenyl)pyrimidinecarboxylic acid (93 mg, 0.35 mmol) in 1,2- roethane (5 mL) was added dimethylamine (2M on in THF, 0.53 mL) at room temperature followed by lar sieves and sodium triacetoxyborohydride (125 mg, 0.59 mmol). After 1.5 hours, acetic acid (31 ul, 0.54 mmol) was added and the reaction stirred at room temperature for 2.5 days. Further dimethylamine (2M solution in THF, 1.0 mL) and sodium triacetoxyborohydride (130mg) were added and the mixture stirred for 6h before a filrther amount of dimethylamine (2M in THF, 1.0 mL), sodium triacetoxyborohydride (130 mg) and AcOH (62 L). The mixture was then stirred for 18 hours. The reaction mixture was filtered and the filtrate was concentrated. A solution of 1:1 (v/v) MeCN:water (0.5 mL) was added to the resulting residue and then concentrated HCl (0.5 mL) was added dropwise. The crude product dissolved and was purified by preparative HPLC (acetonitrile and water) to give 14 mg of an off-white solid. The solid was further purified by sonication in TBME (1 mL) and collected by filtration. The solid was washed with TBME (4 x 1mL) and dried to give the desired compound (7.8 mg, 7.9% yield @ 95% purity) as a off-white solid.
The following compounds were ed substantially as described above.
Molecular Weight Mass Spec Result [M+H]+= 292/294,100% @ rt = 2.00 min Example 19 Reaction Scheme 19 r r l —> —> HZN Stage 1 CT Stage 2 Stage 3 (3' CI CI NAN NAN / OH I / O\/ O O N Stage 4 N CI CI Referring to Reaction Scheme 19, Stage 1. 4-Bromochloroaniline (2.0 g, 9.69 mmol), 1,4-dibromobutane (2.31 ml, 19.4 mmol), ium carbonate (2.68 g, 19.4 mmol), water (25 mL) and e (10 mL) were heated to 1000C overnight with vigorous stirring. The reaction mixture was allowed to cool then extracted with EtOAc (2 x 25 mL). The combined organics were washed with brine (15 mL), dried (MgSO4), filtered and trated to give an orange oil. Column chromatography (Elution: 0-20% EtOAc-heptane) afforded the desired compound (1.16 g, 45% yield) as a yellow oil. SH (500 MHz, DMSO-d6) 7.48 (d, J = 2.36 Hz, 1H), 7.33 (dd, J = 2.36, 8.83 Hz, 1H), 6.87 (d, J = 8.83 Hz, 1H), 3.29 - 3.33 (m, 4H), 1.87 (td, J = 3.43, 6.38 Hz, 4H); Tr (3 min) = 2.68 min m/z (ES+) (M+H)+ 260, 262.
Referring to on Scheme 19, Stage 2. Potassium acetate (1.31 g, 13.4 mmol), bis(pinacolato)diboron (1.36 g, 5.32 mmol) and 1-(4-bromo chlorophenyl)pyrrolidine (1.16 g, 4.45 mmol) were suspended in DMSO (15 mL). The on was degassed with N2 for 5 min. PdCl2(dppf) (0.16 g, 0.22 mmol) was added and the reaction mixture was heated to 80 0C for 3 h. The reaction was cooled to rt.
Water (30 mL) was added to the reaction and the aqueous was extracted using EtOAc (5 x mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried ), filtered, and concentrated to give a black oil. Column chromatography (Elution; 8% EtOAc-heptane) afforded the desired compound (1.14 g, 83% yield) as a pale yellow oil. Tr (3 min) = 2.70 min m/z (ES+) (M+H)+ 307. ] ing to Reaction Scheme 19, Stages 3 & 4 were carried out as described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Molecular Weight Mass Spec Result = 304/306, 100% @ rt = 4.14 min Example 20 Reaction Scheme 20 Br ,.l|\|l+ H2N Br Br N Br 0 —</ Stage 1 Stage 2 HO 0 Stage 3 Stage 4 CI Cl CI o ““1“ ““1“ \ \ OH N BL N O\/ N O _> _> —<O/ _</ _</ Stage 5 0 O Stage 6 0 0' CI Referring to Reaction Scheme 20, Stage 1. In a three neck flask with dropping , thermometer and nitrogen bubbler (no nitrogen input), 4-bromo chlorophenol (5.0 g, 0.024 mol) was fully dissolved in acetic acid (25 mL) at room temperature. Nitric acid (70%, 2.9 mL, 0.048 mol) was added slowly dropwise over approx 15 minutes keeping the temperature at below 300C. The reaction turned orange with an orange precipitate. The reaction was stirred for a filrther 4 hours at 200C. After this time the reaction mixture was cautiously transferred via pipette onto approximately 50 mL ice. Once the ice had melted the yellow precipitate was filtered and washed with water (50 mL). The yellow solid was air dried under vacuum for 1 hour before being dissolved in DCM and dry loaded onto 5.5g silica. The compound was purified by flash column chromatography (elution; 100% heptane, to 20% DCM in heptane, to 40% DCM in e, to 50% DCM in heptanes) to give the desired compound (4.38 g, 72% yield @ 100% UV purity) as a yellow solid. Tr = 1.97min m/z (ES+) no ionisation.
Referring to Reaction Scheme 20, Stage 2. 4-Bromochloro nitrophenol (4.38 g, 17.35 mmol) was ved in ethanol (120 mL). Water (28 mL) and saturated aqueous ammonium chloride (28 mL) were added followed by iron powder (7.75 g, 139 mmol). The on was heated to 500C and stirred for 1 hour, after which time the reaction was cooled to room temperature and filtered through a pad of celite (approx. 5cm in a Jones tube), washing with 50 mL EtOH ed by excess EtOAc until the liquid ran clear. The organic layer was washed with water (50 mL). The water was racted with EtOAc (2 x 200 mL). The ed organic extracts were washed with brine (20 mL), dried ), filtered and concentrated. The resulting residue was dry loaded onto 5g silica and purified by flash column chromatography (elution; 0-30% EtOAc in heptanes) to give the desired compound (2.76g, 72% yield @ 100% UV purity) as a pale brown solid. Tr = 1.65min m/z (ES+) (M+H+) 222/224/226. ing to Reaction Scheme 20, Stage 3. 2-Aminobromo chlorophenol (2.66 g, 11.96 mmol) was dissolved in triethylorthoacetate (24 mL). pTSA monohydrate (0.068 g, 0.359 mmol) was added and the reaction was stirred at 1400C ght. After this time the reaction was cooled to room temperature and the resulting solid was collected by filtration and dried under suction at room temperature for 2 hours to give the title compound (1.58 g, 54% yield @ 100% UV purity) as a white solid. Tr = 2.07min m/z (ES+) (M+H+) 246/248.
Referring to Reaction Scheme 20, Stages 4, 5 & 6 were carried out as described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Molecular Weight Mass Spec Result [M+H]+= 290/292, 100% @ rt = 3.42 min e 21 Reaction Scheme 21 Br Br Br Br fl —> —> HO \/\0 Stage 1 Stage 2 HO Stage 3 HO Cl CI C| Cl Br 'O/K< NAN 0 '/ 0v Stage 4 Stage 5 Stage 6 CI CE?0 0 1 Stage 7 COZNa Referring to Reaction Scheme 21, Stage 1. A solution of 4-br0mo chlorophenol (10.0 g, 48.0 mmol) in anhydrous DMF (30 mL) was added to a stirred suspension of sodium e (2.31 g, 58.0 mmol) in DMF (20 mL) cooled to 00C under nitrogen over 15 min, and stirring continued for 30 min. 3-Bromoprop-l-ene (7.00 g, 58.0 mmol) was added dropwise at 0 0C. After 1 h, the e was allowed to warm to room temperature and then stirred for 3 d. Aqueous saturated NH4C1 (50 mL) was added over 10 min with ice-cooling, and the mixture was concentrated. The e was treated with water (100 mL) and the mixture extracted with ethyl acetate (3 x 120 mL). The combined, dried (NaZSO4) organic extracts were concentrated to give an oil which contained DMF. A solution of the oil in ethyl acetate (100 mL) was washed with water (100 mL) and the dried (Na2SO4) organic layer was concentrated to give the desired compound (11.6 g, 87% yield) as a colourless oil. SH (500 MHz, CDC13) 7.50 (d, J = 2.40 Hz, 1H), 7.30 (dd, J = 2.40, 8.77 Hz, 1H), 6.79 (d, J = 8.78 Hz, 1H), 6.04 (ddt, J = .10, 10.38, 17.14 Hz, 1H), 5.45 (dd, J = 1.44, 17.26 Hz, 1H), 5.32 (dd, J = 1.33, 10.57 Hz, 1H), 4.59 (d, J = 5.10 Hz, 2H).
Referring to Reaction Scheme 21, Stage 2. A solution of l-allyloxy 2-chloro-benzene (90%, 11.6 g, 42 mmol) in mesitylene (200 mL) was heated under nitrogen for 48 h at 190 0C with stirring. The reaction was trated and purified by column chromatography (Elution: 0-10% EtOAc-heptane) to afford the desired compound (4.66 g, 36% yield) as a colourless oil. Tr (3 min) = 2.22 min m/z (ES+) (M+H+) 245, 247.
Referring to Reaction Scheme 21, Stage 3. Sodium periodate (9.04 g, 42.3 mmol) was added to a d mixture of 2-allylbromochloro-phenol (5.23 g, 21 .1 mmol), THF (100 mL) and water (100 mL) at room temperature. After 5 min, osmium tetroxide (13.5 ml of a 0.157 M solution in water, 2.1 mmol) was added and stirring continued for 1.5 h. The mixture was poured into brine (100 mL) and extracted with ethyl acetate (2 x 100 mL) and the combined, dried (Na2SO4) organic extracts were concentrated to give a dark oil. A stirred solution of the dark oil in methanol (100 mL) under nitrogen was cooled to 00C, and treated with sodium borohydride (2.40 g, 63.4 mmol) in small portions over 20 min, ining the temperature between 0 and 10 0C.
After stirring for 16 h, the mixture was concentrated, treated with s lM hydrochloric acid (80 mL) and extracted with ethyl acetate (2 x 100 mL). The combined, dried (Na2SO4) organic ts were concentrated, and the residue purified by column chromatography (Elution: 5-40% EtOAc-heptane) to afford the desired compound (1.60 g, 27% yield) as a less oil. Tr (3 min) = 1.81 min m/z (ES+) (M+H+) 249, 251.
] Referring to Reaction Scheme 21, Stage 4. DIAD (l .52 ml, 7.70 mmol) was added to a stirred solution of ochloro(2-hydroxy-ethyl)-phenol (l .49 g, .92 mmol) and triphenylphosphine (2.02 g, 7.70 mmol) in dry THF (1 .5 mL) under en, with ice-cooling. After stirring for 16 h at rt, the solution was evaporated and the residual oil purified by column chromatography (Elution: 0-lO% EtOAc-heptane) afforded the desired compound (1.20 g, 68% yield) as a colourless oil. Tr (3 min) = 2.27 min m/z (ES+) no ionization.
Referring to Reaction Scheme 21, Stages 5, 6 & 7 were carried out as described in Reaction Scheme 15.
The following compounds were prepared substantially as bed above.
Molecular Weight Mass Spec Result [M+H]+= 277/279, 100% @ rt = 3.53 min Example 22 Reaction Scheme 22 r H + H 2N Br Br Br —> . . %N HO Stage 1 Stage 2 HO H0 Stage 3 HO Cl Cl Cl Cl l Stage 4 N \ OH N BJ§<l Br [>—</ / stages s I: /: Stage 5 & 7 0 0 Cl Cl CI Referring to Reaction Scheme 22, Stage 1. 4-Bromochlorophenol (14.0 g, 0.067 mol) was dissolved in acetic acid (75 mL) at room temperature. Nitric acid (70%, 8.00 ml, 0.145 mol) was added dropwise over approx 30 min keeping the temperature at roughly 20-22 oC. After 1 h at rt, the reaction e was cautiously transferred via pipette onto approx 100 mL ice. Once the ice had melted the yellow itate was filtered, g with a very small volume of water. The yellow solid was dried under suction. Purification by dry flash chromatography (Elution: 0-50% DCM-heptane) afforded the desired compound (12.0 g, 70% yield) as a yellow powder. SH (500 MHz, DMSO) 11.35 (br. s., 1 H) 8.09 (d, J=2.52 Hz, 1 H) 8.07 (d, J=2.52 Hz, 1 H); Tr (3 min) = 1.97 min m/z (ES+) no ionization.
Referring to Reaction Scheme 22, Stage 2. 4-Bromochloro nitrophenol (12.0 g, 47.5 mmol) was dissolved in ethanol (350 mL). Water (80 mL) and saturated aqueous ammonium chloride (80 mL) were added, followed by iron powder (21.2 g, 380 mmol). The reaction was heated to 50 0C and stirred for 2 h. The reaction was cooled to rt and filtered through a prewashed pad of celite, washing with 100 mL EtOH followed by excess EtOAc (approx 1.5 1) until the liquid ran clear. The filtrate was trated to remove organic ts. EtOAc (approx 400 mL) was added to the aqueous residue and the layers were separated. The organic phase was washed with water (150 mL) and brine (100 mL). The aqueous layers were racted with EtOAc (2 x 150 mL). The combined organics were filtered to remove a pale brown solid and evaporated to s to give a purple solid. Dry flash chromatography (Elution: 0-30% EtOAc- heptane) afforded the desired compound (6.5 g, 61% yield) as a pale solid. SH (500 MHz, DMSO) 9.01 (br. s., 1 H) 6.71 (d, J=2.36 Hz, 1 H) 6.66 (d, J=2.36 Hz, 1 H) 5.23 (br. s., 2 H); Tr (3 min) = 1.70 min m/z (ES+) (M+H)+ 222, 224, 226.
Referring to Reaction Scheme 22, Stage 3. 2-Aminobromo chlorophenol (2.04 g, 9.18 mmol) was dissolved in DCM (anhydrous, 30 ml).
Triethylamine (1.6 ml, 11.5 mmol) was added and the reaction was stirred at rt for 1 h under nitrogen. The reaction was cooled in an ice bath for 15 min and then cyclopropanecarbonyl chloride (0.700 mL, 7.65 mmol) was added dropwise over a period of 20 min. The reaction was allowed to gradually warm to rt and stirred for 2 h at rt. The reaction was cooled in an ice bath and an extra 0.2 eq. acid chloride was added se.
The reaction was allowed to warm to rt and stirred at rt for 2 h. DCM (20 mL) was added to the reaction followed by water (50 mL). The organic and aqueous layers were separated. The organic layer was washed with water (3 X 50 mL), brine (30 mL), dried ), filtered and concentrated to give the desired product which was carried forward without further cation.
Referring to Reaction Scheme 22, Stage 4. A crude 4: 1 :1 mixture ofN—(5- bromochlorohydroxyphenyl)cyclopropanecarboxamide, 2-aminobromo phenylcyclopropanecarboxylate and 4-bromochlorocyclopropaneamido ] phenylcyclopropanecarboxylate (2.77 g) was dissolved in toluene (30 mL).
TsOH monohydrate (2.54 g, 13.4 mmol) was added and the reaction was d at 115 0C for 16 h. The reaction was cooled to rt and concentrated to give a brown oil. The e was re-dissolved in EtOAc (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (3 x 100 mL), water (3 x 100 mL), brine (50mL) and dried (MgSO4).
Filtration and concentration gave a brown oil. Column chromatography (Elution: 0-10% heptane) afforded the desired compound (1.18 g, 42%) as an orange crystalline solid. SH (500 MHz, DMSO) 7.85 (d, J=1.73 Hz, 1 H) 7.68 (d, J=1.58 Hz, 1 H) 2.27 - 2.40 (m, 1 H) 1.08 = 2.38 min m/z (ES+) (M+H)+ 272, 274. - 1.38 (m, 4 H); Tr (3 min) Referring to Reaction Scheme 22, Stages 5, 6 & 7 were carried out as described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Molecular Weight Mass Spec Result [M+H]+= 316/318,100% @ rt = 3.84 min Example 23 Reaction Scheme 23 Cl 01 OlStages4Cl N¢\N \N I \ 0H 0 =<O Referring to Reaction Scheme 23, Stage 1. 2-amin0brom0 chlorophenol (2.50 g, 11.2 mmol) was ved in THF (30 m1). CD1 (2.73 g, 16.9 mmol) was added and the on was stirred at 65 0C. After 2 h the reaction was cooled to rt and concentrated to give an orange solid. The residue was redissolved in EtOAc (100 mL) and the organic phase was washed with water (50 mL), 2M HC1 (3 x 50 mL), water (100 mL) and brine (20 mL) and dried (MgSO4). Filtration and concentration afforded the desired compound (2.7 g, 97% yield) as a white solid. SH (500 MHz, DMSO-d6) 12.01 (br. s., 1 H) 7.44 (d, J=1.73 Hz, 1 H) 7.26 (d, J=1.73 Hz, 1 H); Tr (3 min) = 1.87 min m/z (ES-) (M-H)— 246, 248.
Referring to Reaction Scheme 23, Stage 2. 5-Bromoch10ro-2,3-dihydro- 1,3-benzoxaz01one (0.60 g, 2.4 mmol) was dissolved in anhydrous DMF (10 mL) and the on was cooled in an ice bath. Sodium hydride (60% in oil, 0.15 g, 3.6 mmol) was added portionwise and the on was stirred in the ice bath for 1 h. Methyl iodide (0.18 ml, 0.29 mmol) was added and the reaction was stirred at rt for 2 hours. The reaction was cooled in a slush bath. Water (5 mL) was added cautiously followed by EtOAc (20 mL).
The layers were separated. The aqueous was re-extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (10 mL) and brine (10mL) and dried (MgSO4). Filtration and concentration gave a colourless oil. Column tography (Elution: 0-20% EtOAc-heptane) afforded the desired compound (540 mg, 85% yield) as a pink solid. SH (500 MHz, CDCl3) 7.30 (d, J=1.73 Hz, 1 H) 7.03 (d, J=1.73 Hz, 1 H) 3.41 (s, 3 H); Tr (3 min) = 1.97 min m/z (ES+) No ionisation.
Referring to Reaction Scheme 23, Stages 3, 4 & 5 were carried out as described in Reaction Scheme 15.
The following compounds were prepared substantially as bed above. lar Weight Mass Spec Result [M+H]+= 306/308, 98% @ rt = 3.35 min Example 24 on Scheme 24 Br Br Br l —> HO —> O —> Stage 1 Stage 2 I Stage 3 /O 0 Cl Cl Cl N¢\N \ OH /O 0 Referring to Reaction Scheme 24, Stage 1. Methylmagnesium bromide (1.4M in toluene/THF, 1.5 mL, 0.046 mol) was added drop wise over 1 hour to a cold (- 78 0C), stirred solution of 4-bromochlorobenzaldehyde (5.0 g, 0.023 mol) in THF (100 mL) and the mixture was stirred at this temperature under a nitrogen atmosphere for 1 hour. After this time, the reaction e was d to warm to room temperature over 1 hour before being stirred for a further 1.5 hours. The reaction mixture was then cooled to 5 0C in an ice bath and stirred for 10 minutes before saturated ammonium chloride (40 mL) was added drop wise and stirring ued at this temperature for a filrther 10 minutes before being allowed to warm to room temperature. The resulting mixture was then extracted with ethyl e (1 x 100 mL), the c layer was washed sequentially with water (100 mL), and brine (100 mL) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 10% ethyl e, 90% heptanes) to give the desired compound (4.33 g, 81% yield) as a colourless oil. SH (500 MHz, DMSO) 7.64 (d, J =1.58 Hz, 1 H) 7.49 - 7.60 (m, 2 H) 5.47 (d, J = 3.00 Hz, 1 H) 4.96 (dd, J = 6.07, 2.60 Hz, 1 H) 1.28 (d, J = 6.31 Hz, 3 Referring to Reaction Scheme 24, Stage 2. Sodium hydride (60% in oil, 0.38 g, 9.6 mmol) was added portion wise over 5 minutes to a cooled (0 0C), stirred solution of 1-(4-bromochlorophenyl)ethanol (1.5 g, 6.4 mmol) in DMF (15 mL) and the reaction was stirred at this temperature for 20 minutes under a nitrogen atmosphere.
After this time, methyl iodide (0.48 mL, 7.6 mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature before being stirred for a further 18 hours. The reaction was quenched by the drop wise addition of water (15 mL) over 10 minutes and the resulting solution was extracted with ethyl acetate (2 x 30 mL).
The combined c ts were washed sequentially with water (100 mL) and brine (10 mL) before being dried (MgSO4), filtered and concentrated to give the d compound (1.5 g, 99% yield) as a yellow oil. SH (500 MHz, DMSO) 7.71 (d, J=1.89 Hz, 1 H) 7.60 (dd, J=8.35, 1.89 Hz, 1 H) 7.39 (d, J=8.35 Hz, 1 H) 4.63 (q, J=6.46 Hz, 1 H) 3.16 (s, 3 H) 1.26 - 1.38 (m, 3 H).
Referring to Reaction Scheme 24, Stages 3, 4 & 5 were carried out as described in Reaction Scheme 15.
The following compounds were ed substantially as described above.
Molecular Weight Mass Spec Result [M+H]+ = 293/295, 99%@ rt = 3.72 min Example 25 Reaction Scheme 25 Stage 2 I Br Br —» A —> A —> A HzN N Stages 4 Stage 1 H Stage3 N C] C] RI R=CH3orH R=CH3orH Referring to Reaction Scheme 25, Stage 1. [(1- Ethoxycyclopropyl)oxy](trimethyl)silane (5.6 mL, 27.85 mmol) was added drop wise over 10 minutes to a stirred solution of 4-bromochloroaniline (5.0 g, 24.22 mmol) in a e of methanol (50 mL) and acetic acid (95 mL) and the resulting solution was heated to 70 0C and d at this temperature for 4 hours. After this time, the reaction mixture was cooled to room temperature and concentrated. The ing e was then dissolved in THF (25 mL) and added drop wise to a cooled (0 0C), stirred solution of sodium borohydride (l .87 g, 49.4 mmol) and (diethyl ether)(trifluoro)boron (6.2 mL, 48.9 mmol) in THF (50 mL). The resulting mixture was then heated to 70 0C and stirred at this temperature for 4 hours before being cooled to room temperature and allowed to stand overnight. The resulting reaction mixture was quenched by the addition of water (100 mL) before being extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed sequentially with water (100 mL) and brine (100 mL) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified on a Biotage isolera (5% ethyl acetate, 95% heptanes) to give the desired compound (4.8 g, 76% yield) as a colourless oil. Tr = 2.44min m/z (ES+) (M+H+) 246/248.
Referring to Reaction Scheme 25, Stage 2. Sodium hydride (60% dispersion in oil, 0.29 g, 7.28 mmol) was added in one portion to a cooled (0 0C) stirred solution of 4-bromochloro-N-cyclopropylaniline (l .4 g, 5.68 mmol) in dry DMF (35 mL) and the ing solution was stirred for 5 minutes. After this time, thane (0.35 mL, 5.62 mmol) was added and the reaction e was stirred for 10 s before being allowed to warm to room temperature and stirred for a fithher 6 hours under a nitrogen atmosphere. The resulting reaction mixture was extracted with ethyl acetate (3 x 25 mL) and the organic layer washed sequentially with water (75 mL) and brine (75 ml) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified by dry flash chromatography (elution: 100% heptanes) to give the desired compound (1.44 g, 78% yield) as a colourless oil. SH (500 MHz, DMSO) 7.56 (d, J = 2.36 Hz, 1 H), 7.46 (dd, J = 8.67, 2.36 Hz, 1 H), 7.31 (d, J = 8.67 Hz, 1 H), 2.81 (s, 3 H), 2.53 - 2.58 (m, 1 H), 0.63 - 0.69 (m, 2 H), 0.27 - 0.33 (m, 2 H).
Referring to Reaction Scheme 25, Stages 3, 4 & 5 were carried out as described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result \ OH A 289.72 [M+H]+ = 2. 98%@ rt = 3.77 min H CI \ OH AN 0 303.75 [M+H]+= 6. 100% @ rt = 4.40 min CHSCI Example 26 Reaction Scheme 26 HO HO Br Br 0 ofi —> H2N:©/ _. —<\N:Q/ 0 l B40 HZN Stage 1 stage 2 stage 3 —<\Q Cl Cl C] 1 Stages 4&5 N¢\N O \ OH _<\N o Referring to Reaction Scheme 26, Stage 1. Bromine (0.54 mL, 10.4 mmol) was added drop wise to a cooled (0 0C), d solution of ochlorophenol (1.0 g, 6.97 mmol) in DCM (50 mL) and the resulting solution was warmed to room temperature and stirred for 16 hours. After this time, the reaction mixture was cooled in an ice-bath and bromine (0.11 mL, 2.09 mmol) was added before being warmed to room temperature and stirred for a fiarther 1 hour. The resulting solid precipitate was collected by filtration, suspended in DCM (100 mL) and washed with saturated sodium bicarbonate (50 mL). The organic layer was removed, washed sequentially with water (10 mL) and brine (10 mL), before being dried (MgSO4), filtered and concentrated to give the desired compound (1.0 g, 64% yield) as a red solid. SH (500 MHz, DMSO) 10.13 (br. s., 1 H), 6.89 (d, J = 2.21 Hz, 1 H), 6.75 (d, J = 2.21 Hz, 1 H), 4.82 (br. s., 2 H).
] Referring to Reaction Scheme 26, Stage 2. p-Toluene sulfonic acid (0.02 g, 0.12 mmol) was added in one portion to a stirred solution of obromo chlorophenol (0.9 g, 4.05 mmol) in triethylorthoacetate (10 mL) and the resulting reaction mixture was heated to 140 CC and stirred at this temperature for 18 hours. After this time, the reaction mixture was cooled to room temperature and partitioned between water (10 mL) and ethyl acetate (20 mL). The c layer was removed, washed sequentially with water (10 mL), saturated sodium bicarbonate (2 x 20 mL) and brine (10 mL) before being dried (MgSO4), filtered and concentrated. The resulting residue was purified on a Biotage isolera (0% ethyl acetate, 100% heptanes to 40% ethyl acetate, 60% heptanes) to give the desired compound (0.68 g, 48% yield) as a red solid. SH (500 MHz, CDCl3) 7.58 (d, J = 1.42 Hz, 1 H), 7.50 (d, J = 1.58 Hz, 1 H), 2.61 - 2.73 (m, 3 H).
Referring to Reaction Scheme 26, Stages 3, 4 & 5 were carried out as described in on Scheme 15.
The following compounds were ed ntially as bed above. lar Weight Mass Spec Result [M+H]+=290/292 100% @ rt = 3.26min Example 27 The following compounds may be prepared substantially as described above. 6-(3 -chloro {[1-(morpholinyl)propan yl]oxy}phenyl)pyrimidinecarboxylic acid 6-[3-chloro(cyc10propoxymcthy1)phcnyl]pyrimidinc- V’CI 4-carb0xylic acid 6-[3-ch10r0(cyclopropylrncthyl)phcnyl]pyrimidine CI carboxylic acid 6-[3-chlor0(cyclopropylsulfany1)phcnyl]pyrimidine- 4-carb0xylic acid 6-[3-ch10r0(cyclopr0pancsulfinyl)phcnyl]pyrimidine- 4-carb0xylic acid 6-[3-chloro(cyclopropancsulfonyl)phcnyl]pyrimidine- 4-carb0xylic acid 6- {3-ch10r0 pr0py1(hydr0xy)rncthyl]phcnyl}pyrimidine carboxylic acid \ O o O 6-[3-ch10r0(1-cyc10pr0p0xycthyl)phcnyl]pyrirnidinc- CI 4-carb0xylic acid N4\N \ O o 6-(3-chlorocyclopropanccarbonylphcnyl)pyrirnidinc- 0 CI 0xylic acid \ O 0 6-(3 -chlorocyclopropylphcnyl)pyrirnidinc CI carboxylic acid \ 0 AN 0 6-[4-(aziridiny1rncthy1)—3 -chlor0phcnyl]pyrimidine CI carboxylic acid N¢\N \ O A 6- {3-ch10r0 [(dimcthylarnino)rncthyl]phcny1}pyrimidine CI carboxylic acid \ OH AN 0 6-[3-ch10r0(cyclopropylarnino)phcnyl]pyrimidine H CI carboxylic acid \ OH 6- {3-ch10r0 AN 0 [cyc10propy1(rncthyl)amino]phcnyl} pyrimidine CHSCI carboxylic acid 6- {3-ch10r0 [(cyclopropylamino)mcthyl]phcnyl}pyrimidine CI carboxylic acid 6-(3 -chlor0 { [cyc10pr0py1(rncthy1)arnino]methyl}phcnyl)pyrirnidinc- CI 4-carb0xylic acid 6-(7-chlorocyc10propy1—2,3-dihydro-1H-isoindol-5 - yl)pyrirnidinccarb0xy1ic acid 6-[3-ch10r0(furan-Z-y1)phcnyl]pyrirnidinc carboxylic acid 6-[3-ch10r0(1- methoxycyclopropyl)phcnyl]pyrirnidinccarb0xylic CI acid 6-(2,3 -dihydr0-1 ,4-bcnzodioxinyl)pyrirnidinc carboxylic acid 6-(7-chlor0rncthyl-1 ,3 xaz01—5 -y1)pyrimidinc carboxylic acid 6-(7-chlorooxo-2,3-dihydro-1,3-benzoxazol CI yl)pyrimidinccarboxylic acid 6-(7-chloro-3 -rnethy1—2-oxo-2,3 -dihydro-1,3 - azol-S-y1)pyrirnidinecarboxylic acid 6-(7-chlorocyclopropyl-1 ,3-benzoxazol-5 - yl)pyrimidinccarboxylic acid 6- {8-ch10r0irnidazo[ 1 ,2-a]pyridiny1}pyrimidine carboxylic acid 6-(4-ch10r0-1,3 -bcnzoxazolyl)pyrirnidine CI carboxylic acid 6-(quinoliny1)pyrirnidinecarboxylic acid 6-{pyraz010[1,5-a]pyridiny1}pyrimidinecarboxylic acid 6-(4-chloro-3 -cyclopropoxyphcnyl)pyrirnidinc carboxylic acid 6-(4-ch10r0rncthoxyphcnyl)pyrirnidinccarb0xy1ic CI acid 6-[4-ch10r0(pr0panyloxy)phcnyl]pyrirnidinc carboxylic acid 6-[4-chloro(2-rncthy1propoxy)phcnyl]pyrimidine carboxylic acid 6-[4-chlor0(triflu0rorncthoxy)phcnyl]pyrirnidinc ylic acid 6- {4-chlor0-3 -[(1 ,1 1 -trifluoropr0pan y1)0xy]phcnyl}pyrimidinecarboxylic acid 6-(bcnzo [d] [ 1 ,3 ] dioxol-S -y1)pyrirnidinccarboxylic acid N¢\N 6-(2,2-difluorobcnzo [d] [ 1 ,3 ] dioxol-S rirnidinc Fd’o carboxylic acid N¢\N O 6-(2,3-dihydr0bcnzo [b] [1 ,4] dioxiny1)pyrirnidinc K,o carboxylic acid | 6-(7-chlorobcnzo[b]thiophcny1)pyrirnidinc 8 carboxylic acid ksI 6-(7-chlorobcnzo[d]thiazol-5 -y1)pyrirnidinccarboxy1ic acid I 6-(7-chlorobcnzo[d]oxazoly1)pyrirnidinccarboxylic ko acid N\ / 6-(7-chlorobcnzo[c][1,2,5]oxadiazol-5 -y1)pyrirnidinc N/ carboxylic acid 6-(7-chloro-2,3,3a,7a-tetrahydrobenzofuran-S- yl)pyrimidinccarboxylic acid hloro-3a,7a-dihydro-1H-indol-5 -y1)pyrirnidine carboxylic acid 6-(7-chlorornethyl-3 a,7a-dihydr0- 1 H-indazol-S - yl)pyrimidinccarboxylic acid 6-(8-ch10r0quinaz01iny1)pyrirnidinecarb0xy1ic acid 6-(5-ch10r0quinaz01iny1)pyrirnidinecarb0xy1ic acid 6-(8-chlor0quinoxalinyl)pyrimidinecarb0xy1ic acid /=Z 6-(7-ch10r0-1H-bcnzo[d]irnidaz01—5-y1)pyrirnidinc carboxylic acid 6-(3-ch10r0(1-rncthy1cyc10pr0py1)phcnyl)pyrirnidinc- 4-carb0xylic acid 6-(3 -ch10r0(1 - (trifluoromcthyl)cyclopropyl)phcnyl)pyrirnidinc carboxylic acid 6-(3-ch10r0(3 -rncthyloxctan-3 -y1)phcny1)pyrirnidinc- 4-carb0xylic acid 6-(3 -ch10r0(pyrr01idiny1)phcny1)pyrirnidinc carboxylic acid 6-(3-ch10r0(pyrrolidiny1)phcnyl)pyrirnidinc CI carboxylic acid 6-(3-ch10r0(pyrrolidin-Z-yl)phcnyl)pyrirnidinc ylic acid 6-(3 -chlor0(1H-irnidazol-Z-y1)phcnyl)pyrirnidinc carboxylic acid N/ N \ O o hloro(1H-pyrroly1)phenyl)pyrimidine \\ carboxylic acid N CI \ O O 6-(4-tert-buty1—3 -chloropheny1)pyrimidinecarboxy1ic acid N4\N \ o A o 7-chlorocyclopropoxy-5H-chromeno[4,3- 0 0 d]pyrimidinecarboxy1ic acid Example 28 ] A generalized procedure for monitoring renine (KYN) ylation to form product 3-Hydroxy-Kynurenine (3OH—KYN) by LC/MS is described below. Product is quantified by multiple reaction monitoring using MS.
Key reagents: Compound: Stock concentrations: 10mM in 100% DMSO Cell line: CHO GST HIS KMO cell line, 1E4 cells/we11/100u1 in 96we11 cell plate Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration: 10mM in 100 mM potassium phosphate buffer, pH 7.4) Assay conditions: Medium: OptiMem (Reduced Serum Medium 1x, +L-G1utamine + HEPES — Phenol Red; GIBCO: Cat# 11058) Assay Volume: 200 ul Plate Format: 96 well plate, transparent (Corning) Read-Out: product (3OH-KYN) quantification using product c Reader: LC/MS/MS Assay protocol: 0 prepare serial dilution (factor 3) of compound in 100% DMSO (top concentration = 6.67mM, 100% DMSO) [8 points: 6.67mM; 2.22mM; 0.74mM; 0.247mM; 0.082mM; 0.027mM; M; 0.003mM] o prepare 1d concentrated solution of each compound concentration (top concentration 22.22uM, 0.3% DMSO)in OptiMem medium [22.2uM; ; 2.47uM; 0.82 uM; 0.27uM; 0.09uM; 0.03uM; 0.01uM] o prepare substrate (10mM) at concentration of 1.1mM in medium 0 medium of cell plate is drawed off 0 cells are washed with m (100u1/we11) and drawed off again 0 assay mix: 90ul OptiMem/we11+ 90ul compound/well of each concentration [final compound top concentration: 10uM; 0.15%DMSO] [final compound bottom concentration: 0.004uM; 0.15%DMSO] o pre-incubation: 30min at 37°C 0 add 20u1/we11 of the 1.1mM substrate solution (final assay concentration: 100uM) 0 positive control: 200ul OptiMem 0 negative control: 180ul OptiMem + 20ul 1.1mM ate 0 incubate ~24h at 37°C 0 transfer 100ul of each well in a transparent 96we11 plate (Corning) 0 add 100u1/we11 10% trichloro acetic acid (TCA) in water 0 centrifugate plate for 3min at 4000rpm o detect product by LC/MS (injection of 50u1/we11; 2.5f01d l of the 20 ul sample loop) Data analysis: IC50's are calculated using automated fitting algorithm (A+ is).
Example 29 A method of monitoring L-Kynurenine (KYN) hydroxylation to form t 3-Hydroxy-Kynurenine (3OH-KYN) by LC/MS is described below. Product is quantified by multiple reaction monitoring.
Key reagents: Compound: Stock concentrations: 10mM in 100% DMSO Enzyme: KMO enzyme ed at Evotec Via mitochondria isolation from CHO-GST HIS KMO cells Substrate: L-Kynurenine (Sigma: Cat# K3750) [stock concentration: lOmM in 100 mM potassium phosphate buffer, pH 7.4] Assay conditions: Buffer: 100 mM potassium phosphate, pH 7.4, 200uM NADPH, 0.4U/ml G6P-DH (Glucose 6-phosphate dehydrogenase), 3mM G6P (D-Glucose 6-phosphate) Assay Volume: 40 ul Plate Format: 384 well plate, transparent (Matrix) Read-Out: product (3OH-KYN) quantification using product specific : LC/MS/MS Assay protocol: 0 prepare serial dilution (factor 3)of compound in 100% DMSO (top concentration = lOmM, 100% DMSO) [8 points: lOmM; 3.33mM; 1.11mM; 0.37mM; 0.12mM; 0.04mM; 0.0137mM; 0.0045mM, 0.0015mM] o prepare 3.33-fold concentrated solution of each compound concentration (top concentration 300uM, 3% DMSO)in assay buffer [concentrations: 300uM; 100uM; 33.3uM; ll.luM; 3.70uM; 1.23uM; 0.4luM; M] o prepare substrate (lOmM) at tration of lmM in assay buffer 0 assay mix: 4ul nd/well of each concentration + 24ul assay buffer/well + 8 ul KMO human enzyme + 4ul lmM substrate (final concentration=100uM) [final nd top concentration: 30uM; SO] [final compound bottom concentration: 0.0137uM; 0.3%DMSO] 0 positive control: 4ul 50uM FCE28833 in assay buffer [0.5%DMSO] (final assay tration=5uM) + 24ul assay buffer/well + 8ul KMO human enzyme + 4ul lmM substrate (final concentration: 1 00uM) 0 negative l: 28 ul assay buffer/well + 8 ul KMO human enzyme + 4ul lmM substrate (final concentration: 1 00uM) o incubate 400min at RT 0 add 40ul/well 10% trichloro acetic acid in water to stop the assay and precipitate protein 0 centrifuge plate for 3min at 4000rpm 0 product detection by LC/MS (injection of 50ul/well; 2.5fold l of the 20ul sample loop) Data analysis: ICso's are calculated using automated fitting algorithm (A+ Analysis).
Example 30 A method of monitoring renine (KYN) hydroxylation to form 3- Hydroxy-Kynurenine (3OH-KYN) by LC/MS is described. Product is quantified by multiple reaction monitoring (MRM method).
Key reagents: Compound: Stock concentrations: 10mM in 100% DMSO Enzyme: KMO enzyme prepared at Evotec from mouse liver (4-6 weeks old) Via mitochondria isolation as described in the literature Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration: 10mM in 100 mM potassium phosphate buffer, pH 7.4) Assay conditions: Buffer: 100 mM potassium ate, pH 7.4, 200uM NADPH, 0.4U/ml G6P-DH (Glucose 6-phosphate Dehydrogenase), 3mM G6P (D-Glucose phate) Assay Volume: 40 ul Plate Format: 384 well plate, transparent (Matrix) ut: product (3OH-KYN) quantification using product specific Reader: LC/MS/MS Assay protocol: o prepare serial dilution (factor 3)of nd in 100% DMSO (top concentration = 10mM, 100% DMSO) [8 points: 10mM; 3.33mM; 1.11mM; 0.37mM; 0.12mM; ; 0.0137mM; mM, 0.0015mM] prepare 3.33-fold concentrated solution of each compound concentration (top concentration 300uM, 3% DMSO)in assay buffer [concentrations: 300uM; 100uM; 33.3uM; ll.luM; 3.70uM; ; 0.4luM; 0.137uM] prepare substrate (10mM) at concentration of lmM in assay buffer assay mix: 4ul nd/well of each concentration + 24ul assaybuffer/well + 8 ul KMO mouse enzyme + 4ul lmM substrate (final concentration=100uM) [final compound top concentration: 30uM; 0.3%DMSO] [final compound bottom concentration: 0.0137uM; SO] positive control: 4ul SOuM FCE28833 in assay buffer, 0.5%DMSO [final assay concentration=5uM] + 24ul assaybuffer/well + 8 ul KMO mouse enzyme + 4ul lmM substrate [final concentration: 1 00uM] negative control: 28 ul assay buffer/well + 8 ul KMO mouse enzyme + 4ul lmM substrate [final concentration: 1 00uM] incubate 40min at RT add ell 10% trichloro acetic acid in water to stop the assay and precipitate centrifuge plate for 3min at 4000rpm product detection by LC/MS (injection of 20ul/well, 2fold overfill of the 10ul sample loop) Data analysis: IC50's are calculated using automated fitting algorithm (A+ Analysis).
Example 31 Using procedures similar to those bed herein, the following compounds were assayed for activity.
IUPAC name % Inhibition at 10uM* 6-(4-Chloromethoxy-phenyl)-pyrimidinecarboxylic 99.62 acid 6-(3-Aminochloro-phenyl)-pyrimidinecarboxylic 101 .01 acid hloro(tetrahydro-furanyloxy)-phenyl]— 88.39 pyrimidinecarboxylic acid pyridinylamide 6- [4-Chloro-3 -(2-morpholinyl-ethoxy)-phenyl] - 61 .41 pyrimidinecarboxylic acid hydrochloride salt 6-(3 -Chloroisopropyl-phenyl)-pyrimidinecarboxylic 100 acid 6-(3 -Fluoromethyl-phenyl)-pyrimidinecarboxylic l 00 IUPAC name % Inhibition at 10uM* acid 6-(3-Chloroisopropoxy-phcny1)—pyrirnidinc 100 carboxylic acid 6-(3-Chloroisopr0p0xy-phcnyl)rncthyl-pyrirnidinc 70 carboxylic acid 6-(3 -Fluor0rncthy1—phcnyl)—2-rncthy1—pyrirnidinc 96 carboxylic acid 6-(3-Ch10r0cyclopcntyloxy-phcnyl)—pyrirnidinc 97 carboxylic acid 6-(3-Ch10r0trifluor0rncthoxy-phcny1)-pyrirnidinc 100 carboxylic acid 6-(3-F1u0r0isopr0pyl-phcny1)—pyrirnidinccarboxylic 85 acid 6-(4-(R)—scc-Butoxych10r0-phcny1)—pyrirnidinc 100 carboxylic acid 6-(4-(S)—scc-But0xy-3 -ch10r0-phcny1)—pyrimidinc 100 carboxylic acid 6-(3-Chlorocyclopropoxy-phcnyl)-pyrirnidinc 100 carboxylic acid 6- [3 -Ch10r0(2,2,2-trifluor0rncthyl-cthoxy)-phcnyl]- 94 dinecarboxylic acid hlor0cyclopropoxy-phcnyl)—pyridinc-Z- 100 carboxylic acid 6-(4-(R)-scc-Butoxy-3 -ch10r0-phcnyl)-pyridinc 50 carboxylic acid 6-(4-(S)—scc-Butoxychloro-phcnyl)-pyridinc 82 carboxylic acid 4-(3-Chlor0isopropoxy-phcny1)—pyridinc-Z-carboxylic 80 acid 4-(3-Ch10rotrifluororncthoxy-phcnyl)-pyridinc 89 carboxylic acid 6-(3-Chlorocyclobutoxy-phcnyl)-pyrirnidinc 100 carboxylic acid 6- [3 0(2-pipcridiny1-cthoxy)-phcnyl]— 90 pyrimidinecarboxylic acid 6-Quino1iny1-pyrirnidinccarboxy1ic acid 100 6-(8-Ch10ro-chr0rnany1)-pyrirnidinccarboxylic acid 100 6-(7-Chloro-bcnzofurany1)-pyrirnidinccarboxy1ic 100 acid 6-[3-Ch10r0(pyrr01idiny10xy)-phcnyl]-pyrirnidinc 80 carboxylic acid 6-(8-ch10rorncthy1— 1 ,2,3 ,4-tctrahydr0quinolin 100 yl)pyrimidinccarboxylic acid 6-(8-ch10r0quino1iny1)pyrimidinccarboxylatc 100 N-[6-(3-chlorocyclopropoxyphcnyl)pyrirnidin 73 zcncsulfonarnidc N-[6-(3-chlorocyclopropoxyphcnyl)pyrirnidiny1] 98 fluorobcnzcnc-l narnidc N-[6-(3-chlorocyclopropoxyphcnyl)pyrirnidiny1] 88 IUPAC name % Inhibition at 10uM* ororncthoxy)bcnzcncsu1f0narnidc N—[6-(3 -ch10rocyc10propoxyphcny1)pyrirnidiny1] -3 - 77 (trifluororncthoxy)bcnzcncsu1f0narnidc 3 -ch10rocyc10propoxyphcny1)pyrirnidiny1] 96 fluorobcnzcnc- 1 narnidc N—[6-(3 -ch10rocyc10propoxyphcny1)pyrirnidin 33 yl] cyclopropancsulfonamidc 6-(8-ch10r0-1 ,2,3 ,4-tctrahydroquinoliny1)pyrirnidinc 100 carboxylatc 6-(3 -ch10rocyc10propoxyphcny1)-5 -rncthy1pyrirnidinc- 100 4-carboxy1atc 6- {3-ch10ro[2-(rnorph01in 99 y1)cthoxy]phcny1}pyrimidinecarboxy1atc 6- [3 -ch10r0(cyc10propy1rncthoxy)phcny1]pyrirnidinc 101 carboxylatc 6- [3 -ch10r0(0xctan-3 -y10xy)phcny1]pyrirnidinc 100 carboxylatc 4-(3-ch10rocyc10propoxyphcny1)-5H,7H-furo[3 ,4- 100 rnidinonc 6-(3 -ch10rocyc10propoxyphcny1)-5 - 100 (hydroxymcthy1)pyrirnidinccarboxylic acid 4-(3-ch10rocyc10propoxyphcny1)-5H,6H,8H- 100 pyran0[3,4-d]pyrirnidin0nc [(2R,3S,4S,5R)—3,4,5,6-tctrahydr0xy0xany1]rncthy1 6- 102 (3 0cyclopropoxyphcny1)pyrirnidinccarboxy1atc 6- [3 -ch10r0(rncthylsu1fany1)phcny1]pyrimidine 103 carboxylic acid 6- [3 -ch10r0(mcthylsu1finy1)phcny1]pyrirnidinc 100 carboxylic acid 6- [3 -ch10r0(rncthylsu1fony1)phcny1]pyrimidine 100 carboxylic acid 6- {3-ch10r0 90 [cyc10pr0py1(hydr0xy)mcthy1]phcnyl}pyrimidine carboxylic acid 6-(3 -ch10rocyclopropanccarbonylphcny1)pyrirnidinc 101 carboxylic acid 6- [3 -ch10r0(rncthoxyrncthy1)phcny1]pyrirnidinc 105 carboxylic acid 6- [3 -ch10r0(1 -rncthoxycthy1)phcny1]pyrirnidinc 101 carboxylic acid 6- {3-ch10r0 65 [(dimcthylamino)rncthy1]phcny1} pyrimidinecarboxy1ic acid 6- [3 o(cyc10pr0py1arnino)phcny1]pyrirnidinc 101 carboxylic acid 6- {3-ch10r0 96 [cyc10propy1(rncthy1)amino]phcny1} pyrimidine carboxylic acid 6-(3 -ch10r0(pyrr01idiny1)phcny1)pyrirnidinc 100 IUPAC name % Inhibition at 10uM* carboxylic acid 6-(7-chlor0methyl-1,3-benz0xazolyl)pyrimidine 102 carboxylic acid 6-(8-chlor0quin0xalinyl)pyrimidinecarboxylic acid 102 6-(7-chlor0-2,3-dihydrobenz0furan-5 -yl)pyrimidine 102 carboxylic acid 6-(7-chlorocyclopropyl-1,3-benzoxazol-5 - 100 yl)pyrimidinecarboxylic acid 6-(4-chlor0methyl-1,3-benzoxazolyl)pyrimidine 102 carboxylic acid 6-(7-chloromethyloxo-2,3-dihydro-1,3-benzoxazol- 100 -yl)pyrimidinecarb0xylic acid 6-(2H-1,3-benz0di0xolyl)pyrimidinecarboxylic acid 101 * Some portion of activity of amides may be due to contribution of acid precursor.
Example 32: General procedures Method A. Amide coupling. To a on of carboxylic acid (1eq) in DMF were added EDC.HCl (1eq) and HOBt (1 to 1.2eq) or HATU (1 to 1.2eq). The reaction mixture was stirred at t temperature for 30 minutes after which time the riate amine (1eq) was added. The reaction was monitored by LCMS to tion whereupon the reaction e was poured into water. The resultant precipitate was filtered, washed with water (x 2), heptane (x 2) and dried in vacuo to yield the target nd. If a precipitate was not formed the reaction mixture was extracted with EtOAc (x 3) and the combined organic layers were washed with water (x 2), saturated aqueous NaCl (x 2), dried (NaZSO4 or MgSO4) and the solvent removed in vacuo to afford the crude product. Purification was carried out by flash column chromatography, prep HPLC, or a combination of both.
] Method B. Amide coupling. To a solution of carboxylic acid (1eq) in DCM (20vol) under nitrogen were added oxalyl chloride (3eq) and 1 drop ofDMF (cat.).
The reaction mixture was stirred at ambient temperature for 30 minutes after which time the solvents were removed in vacuo. DCM (20vol) or THF ) was added, followed by the required amine (1 to 3eq) and triethylamine (2eq) or DIPEA (1 .5eq). The reaction e was stirred at t temperature. The reaction was monitored by LCMS to completion whereupon water was added. The reaction mixture was then extracted with DCM and the organic layer was washed with water, saturated aqueous NaCl, dried over NaZSO4 or MgSO4 and the solvent removed in vacuo to afford the crude product. ation was carried out by flash column chromatography, prep HPLC, a ation of both or by trituration with an appropriate solvent.
Method C. Amide coupling. To a solution of carboxylic acid (leq) in DMF were added EDC.HCl (leq) and HOBt (leq). The reaction mixture was stirred at ambient temperature for 30 minutes after which time the appropriate amine was added.
The reaction was monitored by LCMS. After completion the reaction mixture was poured into water after which a precipitate came out of solution and was filtered, washed with water, heptane and dried in vacuo to yield the target compound or if a precipitate was not formed the reaction mixture was extracted with EtOAc (3 X) and the combined organic layers were washed with water, saturated aqueous NaCl, dried (NaZSO4 or MgSO4) and the solvent removed in vacuo to afford the crude product. Purification was carried out by flash column chromatography, prep HPLC, or a combination of both.
Method D. Amide coupling. To a solution of carboxylic acid (leq) in DCM (20vol) under nitrogen were added oxalyl chloride (3eq) and DMF (cat). The reaction mixture was stirred at ambient temperature for 30 minutes after which time the ts were removed in vacuo. DCM (20vol) or THF (20vol) was added, followed by the required amine (l to 3eq) and triethylamine (2eq) and the reaction mixture was stirred at ambient temperature. The reaction was monitored by LCMS to completion whereupon water was added. The on mixture was then extracted with DCM and the organic layer was washed with water, saturated s NaCl, dried over NaZSO4 or MgSO4 and the solvent removed in vacuo to afford the crude t. Purification was carried out by flash column chromatography, prep HPLC, a combination of both or by trituration with an riate solvent.
While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the ion. For example, for claim uction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the l language thereof, and it is thus not intended that exemplary embodiments from the cation be read into the claims. Accordingly, it is to be understood that the present invention has been bed by way of illustration and not limitations on the scope of the claims.

Claims (4)

The claims defining the invention are as follows:
1. The compound 6-(3-chlorocyclopropoxy-phenyl)-pyrimidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient.
3. Use of 6-(3-chlorocyclopropoxy-phenyl)-pyrimidinecarboxylic acid, or a ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disorder mediated by Kynurenine oxygenase activity in a subject in need of such a treatment.
4. The use of claim 3 wherein said condition or disorder involves a neurodegenerative pathology.
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